Celltransmissions - Sigma-Aldrich Sigma-RBIp. 11 ... receptor antagonist p. 16 Hydroxyfasudil:...

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New Products pp. 12-15 Antibodies to Potassium Channels p. 10 SR12813: PXR agonist and HMG-CoA reductase inhibitor p. 11 Exo 1: Reversible inhibitor of exocytosis p. 11 DAPT (LY-374973): γ-secretase inhibitor p. 11 YM-53601: Squalene synthase inhibitor p. 11 sPLA 2 inhibitor Available First from Sigma-RBI p. 11 Monoclonal Anti-PML p. 16 Cyclofenil: ERβ estrogen receptor antagonist p. 16 Hydroxyfasudil: Selective rho kinase inhibitor p. 16 Monoclonal Anti-hnRNP-Q p. 17 GGTI-298 and FTI-276: Geranylgeranyl- and farnesyl- transferase inhibitors p. 17 Anti-Radixin p. 17 ICI 63197: Phosphodiesterase IV (PDE IV) inhibitor p. 17 Assay Kits p. 18-19 Topiramate: Novel anticonvulsant and kainate GluR5 receptor antagonist First Available from Sigma-RBI p. 20 SB-408124: Selective non- peptide OX 1 orexin receptor antagonist p. 20 YIC-C8-434: Acyl-CoA: Cholesterol O-Acyltransferase (ACAT) inhibitor p. 20 GW311616A: Human neutrophil elastase (HNE) inhibitor p. 20 Celltransmissions The Newsletter for Cell Signaling and Neuroscience Research Ligands Interacting with Allosteric Sites on G Protein-Coupled Receptors Nigel J.M. Birdsall 2004 Nobel Prize in Chemistry Awarded to Celltransmissions author for the Discovery of Ubiquitin-Mediated Protein Degradation In this Issue... G protein-coupled receptors (GPCRs) are the largest class of cell surface signaling pro- teins in the human genome. Each receptor responds to a specific stimulus, usually the binding of an endogenous ligand, resulting in the generation of intracellular signals that are characteristic of both the nature of the receptor and of the cell. A high percentage of clinically used drugs generate their therapeutic effects by binding to GPCRs. Historically, such drugs have produced their actions by binding to the orthosteric site, i.e. the same site that binds the endogenous signaling molecule. They compete with the endogenous ligand and, depending on their structure, can act as agonists, antagonists or inverse agonists to modulate receptor function. The characteristic of these competitive inter- actions is that a receptor molecule, while occupied by the ligand, will be in a chronically active or inactive state and insensitive to fluctua- tions in the level of the endogenous signaling ligand. For example, a receptor molecule with an agonist bound is chronically activated and gener- ates a continuous signal that may eventually become attenuated by desensitization and down-regulation of the receptor. This mecha- nism means that the spatial and temporal signaling characteristics of naturally operating receptors are lost. This may explain some of the unwanted effects of even highly receptor- selective ligands, especially agonists, caused by their binding to their specific receptor at the 'wrong' time or place. sigma-aldrich.com/cellsignaling continued on page 3 Vol 20, No 3 • January 2005 S igma-RBI, a division of Sigma-Aldrich (NAS- DAQ: SIAL), congratulates the 2004 Nobel laureates in Chemistry, Dr. Avram Hershko, Dr. Irwin Rose and Celltransmissions author Dr. Aaron Ciechanover. Their contributions have led to the realization that protein degradation is a highly controlled process involving the attach- ment of the molecule ubiquitin to unwanted proteins to mark them for disposal. Failure of this system has been implicated in many diseases incuding cervical cancer and cystic fibrosis. continued on page 8
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Transcript of Celltransmissions - Sigma-Aldrich Sigma-RBIp. 11 ... receptor antagonist p. 16 Hydroxyfasudil:...

  • New Products pp. 12-15

    Antibodies to PotassiumChannels p. 10

    SR12813: PXR agonist andHMG-CoA reductase inhibitorp. 11

    Exo 1: Reversible inhibitor ofexocytosis p. 11

    DAPT (LY-374973): -secretaseinhibitor p. 11

    YM-53601: Squalene synthaseinhibitor p. 11

    sPLA2 inhibitor Available Firstfrom Sigma-RBI p. 11

    Monoclonal Anti-PML p. 16

    Cyclofenil: ER estrogenreceptor antagonist p. 16

    Hydroxyfasudil: Selective rhokinase inhibitor p. 16

    Monoclonal Anti-hnRNP-Q p. 17

    GGTI-298 and FTI-276:Geranylgeranyl- and farnesyl-transferase inhibitors p. 17

    Anti-Radixin p. 17

    ICI 63197: PhosphodiesteraseIV (PDE IV) inhibitor p. 17

    Assay Kits p. 18-19

    Topiramate: Novelanticonvulsant and kainateGluR5 receptor antagonistFirst Available from Sigma-RBIp. 20

    SB-408124: Selective non-peptide OX1 orexin receptorantagonist p. 20

    YIC-C8-434: Acyl-CoA:Cholesterol O-Acyltransferase(ACAT) inhibitor p. 20

    GW311616A: Humanneutrophil elastase (HNE)inhibitor p. 20

    CelltransmissionsThe Newsletter for Cell Signaling and Neuroscience Research

    Ligands Interacting with Allosteric Sites on G Protein-Coupled ReceptorsNigel J.M. Birdsall

    2004 Nobel Prize in Chemistry Awarded toCelltransmissions author for the Discovery ofUbiquitin-Mediated Protein Degradation

    In this Issue...

    G protein-coupled receptors (GPCRs) are thelargest class of cell surface signaling pro-teins in the human genome. Each receptorresponds to a specific stimulus, usually thebinding of an endogenous ligand, resulting inthe generation of intracellular signals that arecharacteristic of both the nature of the receptorand of the cell. A high percentage of clinicallyused drugs generate their therapeutic effectsby binding to GPCRs. Historically, such drugshave produced their actions by binding to theorthosteric site, i.e. the same site that binds theendogenous signaling molecule. They competewith the endogenous ligand and, depending ontheir structure, can act as agonists, antagonistsor inverse agonists to modulate receptorfunction.

    The characteristic of these competitive inter-actions is that a receptor molecule, whileoccupied by the ligand, will be in a chronicallyactive or inactive state and insensitive to fluctua-tions in the level of the endogenous signalingligand. For example, a receptor molecule with anagonist bound is chronically activated and gener-ates a continuous signal that may eventuallybecome attenuated by desensitization anddown-regulation of the receptor. This mecha-nism means that the spatial and temporalsignaling characteristics of naturally operatingreceptors are lost. This may explain some of theunwanted effects of even highly receptor-selective ligands, especially agonists, caused bytheir binding to their specific receptor at the'wrong' time or place.

    sigma-aldrich.com/cellsignaling

    continued on page 3

    Vol 20, No 3 January 2005

    Sigma-RBI, a division of Sigma-Aldrich (NAS-DAQ: SIAL), congratulates the 2004 Nobellaureates in Chemistry, Dr. Avram Hershko, Dr.Irwin Rose and Celltransmissions author Dr.Aaron Ciechanover. Their contributions haveled to the realization that protein degradation isa highly controlled process involving the attach-ment of the molecule ubiquitin to unwantedproteins to mark them for disposal. Failure ofthis system has been implicated in many diseasesincuding cervical cancer and cystic fibrosis.

    continued on page 8

    http://www.sigma-aldrich.com/cellsignaling

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    An alternative approach in principle is to target the drugto a second site that is different from the orthosteric site,but which is conformationally linked to the orthosteric site(i.e. an allosteric site). This provides the opportunity to beable to 'tune up' or 'tune down' a receptor response,rather than 'switching' it on (or off) by the use of anorthosteric agonist or antagonist, respectively. Further-more, the allosteric approach can generate novel forms ofselectivity that are absent in orthosteric ligands.

    This approach is well known in the ionotropic receptorfield where for many years drugs such as benzodiazepines,acting allosterically to enhance the actions of -aminobutyric acid (GABA) at GABAA receptors, have had clinicalutility. However, even in this well-established field, it hasproven difficult until recently to generate allosteric ligandsthat are selective in their actions on a given subtype ofGABAA receptors [1,2]. In the past few years there havebeen substantial and increasing scientific efforts directedtowards the detection and characterization of allostericsites on a number of GPCRs, as well as the accompanyingdiscovery and development of molecules that begin todefine the pharmacology of these sites. The purpose ofthis article is to provide a compilation of some of theallosteric ligands that act at GPCRs and a flavor of thenovel selectivities associated with this type of ligand. A number of reviews of this field have been publishedrecently [3-8].

    Analysis of Allosteric Interactions: TheAllosteric Ternary Complex ModelFigure 1 represents the simplest model that describes anallosteric interaction between two ligands, L and X, at areceptor, R. This is a symmetrical scheme but, for thepurposes of this article, L will be defined as an orthostericligand and X as the allosteric ligand.

    In this model there are two topographically separatedbinding sites on the receptor (R) that are conforma-tionally linked. Orthosteric ligands (L) including, and mostimportantly, the endogenous hormone or neurotrans-mitter bind to one site with an affinity constant KL. Thebinding of ligands (X) to the second site allostericallymodulates the affinity of L by a factor , the coopera-tivity factor. In a complementary manner, the binding of Lto the receptor changes the affinity constant of X from

    KX (in the absence of L) to .KX (in the presence of highconcentrations of L). If > 1, there is positive hetero-tropic cooperativity, if < 1, there is a negative coopera-tive interaction between L and X. For the very specialcase where = 1, there is neutral cooperativity and thebinding of X to R does not affect the equilibrium bindingof L. Therefore, the binding and actions of an allostericligand with any given L and R are defined by two param-eters, its affinity KX (which is independent of L) and itscooperativity (which depends on L). The selectivity andthe pharmacological activity of X at different receptors istherefore manifest by differences in either or both KL and. The importance is that there are two very differentindependent parameters (affinity and cooperativity) thatcan generate receptor selectivity.

    In equilibrium binding studies it is possible to measure KXand (and hence .KX) for an allosteric ligand. Analyticalmethods by which these parameters can be visualized andcalculated have been devised [9-12]. Allosteric ligands arealso generally found to modulate the dissociation rate ofradioligands bound to the orthosteric site because thedissociation rate constants of L from R.L and X.R.L wouldbe expected to be different. This effect on radioligandkinetics generates a second estimate of .KX which shouldbe the same as that determined in the equilibrium experi-ment if the ternary complex describes the L-R-X interactionand the effects of X on the binding of L are not simply dueto non-specific effects of X, such as membrane perturba-tion. We have used these approaches to confirm thevalidity of the allosteric ternary complex model for thebinding of allosteric ligands to a number of GPCRs [10-19].

    The allosteric ternary complex model can also be used toanalyze functional data [10-12,20]. However, it has to beassumed that X has no intrinsic activity and the binding ofX to the receptor only changes agonist 'affinity', but doesnot affect agonist 'efficacy'. If this is not so, the estimatesof the cooperativity obtained using this simple model toanalyze binding and functional data may differ from eachother. Under such circumstances more complex models,involving receptor isomerization states and/or the ability ofallosteric ligands to couple to and uncouple from G proteins,need to be considered [7,21-23].

    Novel Selectivities Associated withAllosteric Ligands (Table 1)It is of prime importance to characterize the interactionsbetween an allosteric ligand and the endogenous signalingmolecule(s) at GPCRs as these are the only allosteric inter-actions that are generally going to be therapeutically use-ful in vivo. As stated earlier, different allosteric ligands actto tune up or tune down endogenous signaling by thereceptor. If ligand X has no intrinsic activity, it has noaction on its own and therefore, silent receptors are notaffected by allosteric ligands. This provides temporal aswell as spatial resolution for the actions of the allosteric

    Ligands Interacting with Allosteric Sites on G Protein-Coupled ReceptorsNigel J.M. Birdsall (continued from cover)

    KL

    .KX

    X.R.LX.R + L

    KX

    R + L+ +X XKL

    R.L

    Figure 1. The allosteric ternary complex model.

    http://www.sigma-aldrich.com/cellsignaling

  • ligand. In contrast, agonists provide no such resolution andthis can lead to potential unwanted effects caused by'inappropriate' and chronic stimulation of the target receptor.

    Furthermore, allosteric ligands have a limited maximumactivity that is determined by the value of their coopera-tivity. It might be anticipated that an allosteric ligandthat exhibits positive cooperativity with the endogenousligand (an allosteric enhancer) could be of therapeuticuse in diseases where a focal deficit in neurotransmitterlevel gives rise to symptoms of the disease. Examples areAlzheimers disease, where there is a cholinergic deficitin the cerebral cortex and hippocampus, and Parkinsonsdisease where there are low levels of dopamine in thebasal ganglia. Allosteric enhancers should produce aselective boost in signaling in those regions of lowneurotransmitter release.

    Receptor subtypes are closely homologous proteins that areactivated by the same endogenous ligand and thus arelikely to have a conserved orthosteric site. This can result indifficulties in designing subtype-selective ligands, especiallyagonists. In contrast, an allosteric binding site on a recep-tor may not have been subject to the same evolutionarypressure to conserve its structure and hence there is theincreased possibility of allosteric ligands that exhibitselectivity based on affinity.

    A much more subtle, but nevertheless profound, form ofselectivity is that based on a ligand having different coop-erativities for different receptor species, especially receptorsubtypes. In this case, the important feature of an allostericligand is that if it has neutral cooperativity with theendogenous neurotransmitter at one receptor subtype itwill be totally inactive at that subtype even though it bindsto the receptor. It will have no action on that receptor atany concentration. If this allosteric ligand exhibits positiveor negative cooperativity with the same endogenous ligandat another subtype, it will have an action at that subtype.The form of selectivity, that is action at one subtype, noaction at another subtype at any concentration, has beentermed absolute subtype selectivity [11,12]. Subtypeselectivity, based on cooperativity, was first described forbrucine analogs that bind to an allosteric site on muscarinicreceptors [11,12]. Subsequently thiochrome, an oxidationproduct and metabolite of thiamine, was shown to demon-strate absolute subtype selectivity, being an allostericenhancer at M4 muscarinic acetylcholine receptors, buthaving no effect on acetylcholine binding at the other fourmuscarinic receptor subtypes [24].

    Allosteric LigandsTable 2 (pages 6 and 7) presents a list of GPCRs that havebeen claimed to possess allosteric sites together withselected ligands that have been used to characterize thesesites. In a number of examples, the data are limited and/ornot capable of simple interpretation in terms of allosterism.Further characterization of these ligand-receptor interac-tions would be beneficial.

    The receptors listed in Table 2 are primarily members oftwo of the three major subclasses of GPCRs: namely class-es A and C. The only class B receptor reported to have awell-defined allosteric site is the CRF1 corticotrophin releas-ing factor receptor [25]. In the case of class C receptors thefocus, driven primarily by the pharmaceutical industry, hasbeen on the GABAB receptor, the metabotropic glutamatereceptor subtypes and the calcium-sensing receptor.Allosteric enhancers of binding and function at GABABreceptors, CGP-7930 (Prod. Code C 0862) [22], CGP-13501(Prod. Code C 0987) [22] and GS39783 (Prod Code G 5919)[26], have been reported. The latter compound has ananxiolytic effect in a rodent model without displaying someof the undesirable side effects produced by either baclofenor the benzodiazepines [27]. Selective allosteric enhancersat each of subtypes 1,2,4 and 5 of metabotropic glutamatemGlu receptors have also been described.

    The calcium-sensing receptor represents the only GPCR forwhich an allosteric ligand (Cinacalcet, an allostericenhancer) has been approved by the FDA for the treatmentof secondary hyperparathyroidism in patients with chronickidney disease on dialysis, and hypercalcemia in patientswith parathyroid cancer [28-30]. It acts by increasing thesensitivity of the receptor to circulating calcium and conse-quently reducing parathyroid hormone release thereby nor-malizing serum calcium levels. Of the family A (rhodopsin-like) receptors, most investigations have involved the dis-covery of allosteric muscarinic ligands and the investigationof their mechanisms of action. In the case of muscarinicreceptors, it has been demonstrated that there are twoallosteric sites with very different pharmacologies [15,16].A similar spatial separation of the L-amino acid and thecalcimimetic binding sites on the calcium-sensing receptorhas also been demonstrated [31]. For some allostericmuscarinic ligands, e.g. tacrine (Prod. Code A 3773) andsome pentacyclic carbazolones, the allosteric interactionsexhibit slope factors greater than 1 and less than 2, indi-cating a positively homotropic cooperative interaction. Ithas been suggested that these ligands may be modulatingreceptor-receptor interactions in a receptor dimer [13,32].

    Studies on muscarinic receptors and A1 adenosine recep-tors have indicated that certain allosteric ligands may haveintrinsic activity. The best example is PD 81,723, the firstallosteric enhancer reported to act at a GPCR (A1 adeno-sine receptors) [33]. This ligand also displays agonist activityin the absence of an orthosteric ligand. Therefore, it has a

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    rsLigands Interacting with Allosteric Sites... (continued)

    Table 1. Potential novel selectivities associated with allosteric ligands

    Maximum effect limited by the cooperativity factor No activation of silent receptors-spatial and temporal selectivity of action Potential for greater subtype selectivity based on affinity Subtype selectivity based on cooperativity Ability to modulate receptor-protein and receptor-receptor interactions by

    a small molecule binding to an allosteric site

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  • dual action as allosteric enhancer and allosteric agonist. Incontrast, alcuronium acts as an inverse agonist on functionat M2 muscarinic receptors [34]. It decreases the efficacyof pilocarpine to such an extent that this partial agonistbecomes an antagonist. This is an example of an allostericligand changing the pharmacology of an orthostericligand. Some other allosteric ligands, e.g. 6-methyl-2-(phenylethynyl)pyridine (MPEP; Prod. Code M 5435)acting at mGlu5 receptors, have also inverse agonist activi-ty and decrease agonist efficacy [35]. Another cholinergicagonist, McN-A-343 (Prod. Code C 7041) has been shownto interact allosterically at M2 muscarinic receptors and itwas speculated at that time that it might also be able toactivate the receptor from the allosteric site [36]. Morerecently, the atypical muscarinic agonists, AC-42 [37],clozapine (Prod. Code C 6305) and N-desmethylclozap-ine (Prod. Code D 5676) [38] have been reported toexhibit a subtype selectivity that is greater than thatusually observed for muscarinic agonists. They appear tobind in a different mode to acetylcholine and, on thatbasis, it has been hypothesized that they also may activatethe muscarinic receptor from an allosteric site. However,direct evidence for such a mechanism is lacking at present.Some allosteric ligands seem to act allosterically at many classA GPCRs. The two notable examples are amilorides thatinteract at adenosine, dopamine and -adrenoceptor sub-types [17-19, 39-42]. An even greater promiscuity and com-plexity is shown by SCH-202676 (Prod. Code S 4063) whichinteracts with adrenergic, dopamine, muscarinic and opioidreceptor subtypes [43,44]. The findings suggest that theseligands may interact with a binding site (or sites) that is con-served between at least some members of class A GPCRs.

    A question that is often asked is whether there should bean endogenous ligand if there is a well-defined allostericsite on a GPCR. At present there is very limited evidence tosupport such a hypothesis, although the actions of zinc (at2-adrenoceptors [45] and D1/D2 dopamine receptors [46]), L-amino acids (calcium sensing receptor [47]), oleamide(Prod. Code O 2136; 5-HT2A [48] and 5-HT7 serotoninreceptors [49]) and 5-HT-moduline, an endogenoustetrapeptide LSAL, (at 5-HT1B/1D serotonin receptors[50,51]) are suggestive that this may be so.

    SummaryAllosteric ligands, especially allosteric enhancers, have thepotential for exhibiting different selectivities at GPCRs fromthose of orthosteric ligands. The difficulty is that, at theinitiation of a project, the information about the pharma-cology of an allosteric site on a GPCR may be very limitedor non-existent. In addition, as the effects of an allostericligand on receptor binding or function may be small, anyscreening assay must be very sensitive and robust in orderto detect 'hits'. Equally, the actions of allosteric ligands invivo may be more subtle and different from those oforthosteric ligands. Nevertheless the large number ofrecent publications provides strong evidence of an increas-ing interest from both academia, and especially the

    pharmaceutical industry. The recent approval of Cinacalcetfor clinical use supports allosteric modulation at GPCRs asa valid and novel therapeutic approach.

    References1. Street, L.J., et al., J. Med. Chem., 47, 3642-3657 (2004).2. Whiting, P.J., Drug Discov. Today, 8, 445-450 (2003).3. Christopoulos, A., Nat. Rev. Drug Discov., 1, 198-209 (2002).4. Soudijn, W.S., et al., Drug Discov. Today, 9, 754-758 (2002).5. Christopoulos, A. and Kenakin, T., Pharmacol. Rev., 54, 323-374 (2002).6. Jensen, A.A. and Spalding, T.A., Eur. J. Pharmacol. Sci., 21, 407-420 (2004).7. May, L.T., et al., Curr. Pharmaceut. Design, 10, 2003-2013 (2004).8. Pin, J-P., et al., Mol. Pharmacol., 60, 881-884 (2001).9. Stockton, J.M., et al., Mol. Pharmacol., 23, 551-557 (1983).10. Lazareno, S. and Birdsall, N.J.M., Mol. Pharmacol., 48, 362-378 (1995).11. Lazareno, S., et al., Mol. Pharmacol., 53, 573-589 (1998).12. Birdsall, N.J.M., et al., Mol. Pharmacol., 55, 778-786 (1999).13. Gharagozloo, P., et al., J. Med. Chem., 45, 1259-1274 (2002).14. Lazareno, S., et al., Life Sci., 64, 519-526 (1999).15. Lazareno, S., et al., Mol. Pharmacol., 58, 194-207 (2000).16. Lazareno, S., et al., Mol. Pharmacol., 62, 1492-1505 (2002).17. Leppik, R.A., et al., Mol. Pharmacol., 53, 916-925 (1998).18. Leppik, R.A., et al., Mol. Pharmacol., 57, 436-445 (2000).19. Leppik, R.A. and Birdsall, N.J.M., Mol. Pharmacol., 58, 1091-1099 (2000).20. Ehlert, F.J., Mol. Pharmacol., 33, 187-194 (1988).21. Hall, D.A., Mol. Pharmacol., 58, 1412-1423 (2000).22. Urwyler, S., et al., Mol. Pharmacol., 60, 963-971 (2001).23. Parmentier, M-L., et al., Trends Pharmacol. Sci., 23, 268-274 (2002).24. Lazareno, S., et al., Mol. Pharmacol., 65, 257-266 (2004).25. Hoare, S,R.J., et al., Mol. Pharmacol., 63, 751-765 (2003).26. Urwyler, S., et al., J. Pharmacol. Exp. Ther., 307 322-330 (2003).27. Cryan, J.F., et al., J. Pharmacol. Exp. Ther., 310, 952-963 (2004).28. Nemeth, E.F., Cell Calcium, 35, 283-289 (2004).29. Shoback, D.M., et al., J. Clin. Endocrinol. Metab., 88, 5644-5649 (2003).30. Block, G.A., et al., New Engl. J. Med., 350, 1516-1525 (2004).31. Zhang, Z., et al., J. Biol. Chem., 277, 33736-33741 (2002).32. Potter, L.T., et al., Mol. Pharmacol., 35, 652-660 (1989).33. Bruns, R.F. and Fergus, J.H., Mol. Pharmacol., 38, 939-949 (1990).34. Zahn, K., et al., J. Pharmacol. Exp. Ther., 301, 720-728 (2002).35. Pagano, A., et al., J. Biol. Chem., 275, 33750-33758 (2000).36. Birdsall, N.J.M., et al., Br. J. Pharmacol., 78, 257-259 (1983).37. Spalding, T.A., et al., Mol. Pharmacol., 61, 1297-1302 (2001).38. Sur, C., et al., Proc. Natl. Acad. Sci. USA, 100, 13674-13679 (2003).39. Gao, Z., IJzerman, A.P., Biochem. Pharmacol., 60, 669-676 (2000).40. Gao, Z.G., et al., Biochem. Pharmacol., 65, 525-534 (2003).41. Hoare, S.R.J. and Strange, P.G., Mol. Pharmacol., 50, 1295-1308 (1996).42. Hoare, S.R.J., et al., Br. J. Pharmacol., 130, 1045-1059 (2000).43. Fawzi, A.B., et al., Mol. Pharmacol., 59, 30-37 (2001).44. Lanzafame, A. and Christopoulos, A., J. Pharmacol. Exp. Ther., 308, 830-837

    (2004).45. Swaminath, G., et al., Mol. Pharmacol., 61, 65-72 (2002).46. Schetz, J.A. and Sibley, D.R., J. Neurochem., 68, 1990-1997 (1997).47. Conigrave, A.D., et al., Proc. Natl. Acad. Sci. USA, 97, 4814-4819 (2000).48. Thomas, E.A., et al., Proc. Natl. Acad. Sci. USA, 94, 14115-14119 (1997).49. Hedlund, P.B., et al., Biochem. Pharmacol., 58, 1807-1813 (1999).50. Fillion, G., et al., Behav. Brain Res., 73, 313-317 (1996).51. Massot, O., et al., Ann. NY Acad. Sci., 861, 174-182 (1998).52. Bhattacharya, S. and Linden, J., Biochim. Biophys. Acta, 1265, 15-21 (1995).53. Kollias-Baker, C.A., et al., J. Pharmacol. Exp. Ther., 281, 761-768 (1997).54. Kourounakis, A., et al., Biochem. Pharmacol., 61, 137-144 (2001).55. Musser, B., et al., J. Pharmacol. Exp. Ther., 288, 446-454 (1999).56. Gao, Z.G., et al., Mol. Pharmacol., 60, 1057-1063 (2001).57. Gao, Z.G., et al., Mol. Pharmacol., 62, 81-89 (2002).58. Waugh, D.J., et al., J. Pharmacol. Exp. Ther., 291, 1164-1171 (1999).59. Molderings, G.J., Br. J. Pharmacol., 130, 1706-1712 (2000).60. Hammerland, L.G., et al., Mol. Pharmacol., 53, 1083-1088 (1998).61. Nemeth, E.F., J. Mol. Endocrinol., 29, 15-21 (2000).62. Petrel, C., et al., J. Biol. Chem., 279, 18990-18997 (2004).63. Sabroe, I., et al., J. Biol. Chem., 275, 25985-25992 (2000).64. Zhao, J., et al., J. Exp. Med., 190, 101-111 (1999).65. Bertini, R., et al., Proc. Natl. Acad. Sci. USA, 101, 11791-11796 (2004).66. Cox, M.A., et al., Mol. Pharmacol., 59, 707-715 (2001).67. Talbodec, A., et al., Mol. Pharmacol., 57, 797-804 (2000).68. Blandin, V., et al., Mol. Pharmacol., 58, 1461-1469 (2000).69. Carroll, F.Y., et al., Mol. Pharmacol., 59, 965-973 (2001).70. Litschig, S., et al., Mol. Pharmacol., 55, 453-461 (1999).71. Lavreysen, H., et al., Mol. Pharmacol., 63, 1082-1093 (2003).72. Malherbe, P., et al., J. Biol. Chem., 278, 8340-8347 (2003).73. Knoflach, F., et al., Proc. Natl. Acad. Sci. USA, 98, 13402-13407 (2001).74. Johnson, M.P., et al., J. Med. Chem., 46, 3189-3192 (2003).

    Ligands Interacting with Allosteric Sites... (continued)

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    References (continued on page 8)

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    Ligands Interacting with Allosteric Sites... (continued)

    Receptor Subtype Ligands Allosteric Effect Prod. Code References

    Adenosine

    A1 PD 81,723 Positive [33,52-55]

    Amilorides Negative A 7410 [40]

    A2A Amilorides Negative A 7410 [39]

    A3 VU5455 Positive [56]

    VU8504 Positive [56]

    DU124183 Positive [57]

    Adrenoceptor

    1A Benzodiazepines Positive [58]

    Amilorides Negative A 7410 [18]

    2A Amilorides Negative A 7410 [17,19]

    2D Agmatine Positive A 7127 [59]

    2 Zinc Positive A 6014 [43]

    Calcium-Sensing

    NPS 467 Positive [60]

    NPS 568 Positive [60]

    AMG 073 [Cinacalcet] Positive [28-30]

    NPS 2143 Negative [61]

    Calhex231 Negative [62]

    L-Amino acids Positive [31,47]

    Chemokine

    CCR1/3 UCB35625 Negative [63]

    CCR4/5 Trichosanthin Positive [64]

    CXCR1/2 Repertaxin Negative [65]

    CXCR3 IP-10 Negative C 8490 [66]

    CXCR3 I-TAC Negative [66]

    CXCR4 Trichosanthin Positive [64]

    CorticotrophinReleasing Factor CRF1 Antalarmin Negative A 8727 [25]

    NBI 27914 Negative N 3911 [25]

    NBI 35965 Negative [25]

    DMP-696 Negative [25]

    Dopamine

    D1/2 Zinc Negative A 6014 [46]

    D2/3/4 Amilorides Negative A 7410 [41,42]

    Endothelin

    ETA Aspirin Negative A 5376 [67]

    Salicylic acids Negative [67,68]

    GABABCGP-7930 Positive C 0862 [22]

    CGP-13501 Positive C 0987 [22]

    GS39783 Positive G 5919 [26,27]

    Table 2. Some allosteric ligands that act as GPCRs.Positive: refers to enhancement of agonist/endogenous ligand binding and/or functionNegative: refers to allosteric inhibition of agonist/endogenous ligand binding and/or functionNeutral: refers to neutral cooperativity with acetylcholine

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  • Ligands Interacting with Allosteric Sites... (continued)

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    Receptor Subtype Ligands Allosteric Effect Prod. Code References

    Glutamate

    mGlu1 BAY 36-7620 Negative [69,70]

    CPCCOEt Negative C 9611 [70,71]

    R214127 Negative [71]

    NPS 2390 Negative N 4786 [71]

    EM-TBPC Negative [72]

    Ro 01-6128 Positive [73]

    Ro 67-7476 Positive [73]

    mGlu2 LY-487379 Positive [74]

    LY-181837 Positive [75]

    Phenyl-tetrazolyl acetophenones Positive [76]

    mGlu4 SIB1893 Positive S 9311 [77]

    MPEP Positive M 5435 [77]

    ()-PHCCC Positive [78,79]

    mGlu5 MPEP Negative M 5435 [35]

    3,3'-Difluorobenzaldazine Positive [80]

    CPHHA Positive [81]

    Muscarinic

    M1-M5 Gallamine Negative G 8134 [9,82]

    Alcuronium Negative [83]

    Strychnine Negative S 0532, S 8753 [10]

    Brucine Positive M1 B 0253 [11,12]

    Brucine N-oxide Positive M3/4 R158658 [11,12]

    W-84 Negative [84]

    Staurosporine Negative S 4400 [15]

    KT 5720 Positive M1 K 3761 [15]

    WIN 51,708 Negative W-103 [16]

    WIN 62,577 Positive M3 W-104 [16]

    Thiochrome Positive M4 T 7891 [24]Neutral M1/2/3/5

    Tacrine Negative A 3773 [32]

    McN-A-343 Negative C 7041 [36]

    Neurokinin

    NK1 Heparin Positive H 0777, H 3393 [85]

    Purine

    P2Y1 2,2'-Pyridylisatogen tosylate Negative [86-88]

    Serotonin

    5-HT1B/D 5-HT Moduline Negative [50,51]

    5-HT2A Oleamide Positive O 2136 [48]

    5-HT2C PNU-69176E Positive [89]

    5-HT7 Oleamide Negative O 2136 [48,49]

    Table 2. Some allosteric ligands that act as GPCRs. (continued)Positive: refers to enhancement of agonist/endogenous ligand binding and/or functionNegative: refers to allosteric inhibition of agonist/endogenous ligand binding and/or functionNeutral: refers to neutral cooperativity with acetylcholine

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    References (continued from page 5)75. Barda, D.A., et al., Bioorg. Med. Chem. Lett., 14, 3099-3102 (2004).76. Pinkerton, A.B., et al., J. Med. Chem., 47, 4595-4599 (2004).77. Mathiesen, J.M., et al., Br. J. Pharmacol., 138, 1026-1030 (2003).78. Maj, M., et al., Neuropharmacology, 45, 895-906 (2003).79. Marino, M.J., et al., Proc. Natl. Acad. Sci. USA, 100, 13668-13673 (2003).80. O'Brien, J.A., et al., Mol. Pharmacol., 64, 731-740 (2003).81. O'Brien, J.A., et al., J. Pharmacol. Exp. Ther., 309, 568-577 (2004).82. Clark, A.L. and Mitchelson, F., Br. J. Pharmacol., 58, 323-331 (1976).83. Proska, J. and Tucek, S., Mol. Pharmacol., 45, 709-717 (1994).84. Lllman, H., et al., Eur. J. Pharmacol., 6, 241-247 (1969).85. Knaus, G.A., et al., Eur. J. Pharmacol., 207, 267-270 (1991).86. Spedding, M., et al., Br. J. Pharmacol., 53, 575-583 (1975).87. King, B.F., et al., Br. J. Pharmacol., 117, 1111-1118 (1996).88. Gao, Z.G., et al., Biochem. Pharmacol., 68, 231-237 (2004).89. Im, W.B., et al., Mol. Pharmacol., 64, 78-84 (2003).

    Ligands Interacting with Allosteric Sites... (continued)

    Antibodies

    A-268 Anti-A1 Adenosine Receptor

    A-269 Anti-A2A Adenosine Receptor

    A-270 Anti-1 Adrenergic Receptor

    A-271 Anti-1 Adrenergic Receptor

    D-187 Monoclonal Anti-D1 Dopamine Receptor, Clone 1-1-F11 s.E6

    E 3651 Anti-ETA Endothelin Receptor

    G 5915 Anti-GABAB Receptor

    G 5293 Anti-phospho-GABAB Receptor [pSer892] R2 Subunit

    G 9665 Anti-Glutamate Receptor 1A, Metabotropic (mGluR1A)

    G 9790 Anti-Glutamate Receptor 2/3, Metabotropic(mGluR2/3)

    G 9915 Anti-Glutamate Receptor 5, Metabotropic (mGluR5)

    M 9808 Anti-Muscarinic Acetylcholine Receptor (M1)

    M 9558 Anti-Muscarinic Acetylcholine Receptor (M2)

    M-272 Monoclonal Anti-Muscarinic Acetylcholine Receptor(M2), Clone 31-1D1

    P 6487 Anti-P2Y1 Purinergic Receptor

    S 4812 Anti-5-HT2A Serotonin Receptor

    S 5062 Anti-5-HT7 Serotonin Receptor

    S 8305 Anti-NK1 Tachykinin (Substance P) Receptor

    Receptors

    E-005 Benzodiazepine Receptor

    D-152 D3 Dopamine Receptor, human

    D-181 D3 Dopamine Receptor, rat

    A-213 2A Adrenergic Receptor

    D-178 D1 Dopamine Receptor

    D-180 D2long Dopamine Receptor

    D-177 D4.2 Dopamine Receptor, human, CHO cells

    D 2439 D4.2 Dopamine Receptor, human, Sf9 cells

    M 4560 M2 Muscarinic Acetylcholine Receptor

    M-176 M3 Muscarinic Acetylcholine Receptor

    M 4810 M4 Muscarinic Acetylcholine Receptor

    S -177 5-HT7 Serotonin Receptor, human

    S-162 5-HT7 Serotonin Receptor, rat

    GPCR Receptors and Antibodies available from Sigma-RBI

    About the AuthorNigel Birdsall received his graduate and postgraduate degreesfrom Cambridge University. After postdoctoral research on thechemical mechanisms of carcinogenesis at the Sloan-KetteringInstitute for Cancer Research in New York, he returned toCambridge and the new MRC Molecular Pharmacology Unit.There he studied the structure and dynamics of lipids and lipid-protein interactions in membranes, primarily using NMR tech-niques. He relocated to the National Institute for Medical Researchat Mill Hill in London and began to investigate the detailed bind-ing and functional properties of G protein-coupled receptors,especially muscarinic acetylcholine receptors. He is currentlyProgram Leader in the Division of Physical Biochemistry at NIMRand an Honorary Reader in Pharmacology at University College,London.

    Sigma-RBI is especially proud of its association with Dr.Ciechanover who in September 2003 authored an articleentitled The Ubiquitin-Proteasome System: Death ofProteins is Required for Life of Cells for the divisionsquarterly Celltransmissions cell signaling newsletter. Dr.Ciechanover is currently director of the Rappaport FamilyInstitute for Research in Medical Sciences at the Technion(Israel Institute of Technology) in Haifa, Israel.

    We feel honored to be able to include Dr. Ciechanoveramong our Celltransmissions authors, stated Dr. KeithWatling, Director of Sigma-RBI, His landmark discoveries,together with Drs. Hershko and Rose, have provided criticalinsight into how proteins are degraded and disposed ofinside the cell.

    Sigma-RBI is the leading supplier of products for ubiquitin-proteasome and cell stress research. Our product lineincludes ubiquitin proteins, inhibitors and antibodies, pro-teosome fractions and a range of enzymes, inhibitors andantibodies for nitric oxide, cell stress and protein degrada-tion research.

    For more information, please visit:www.sigma-aldrich.com/ubiquitin-proteasome

    2004 Nobel Prize in Chemistryawarded to Celltransmissionsauthor for the discovery ofubiquitin-mediated proteindegradation continued from cover

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    Antibodies to Potassium Channels

    Antibodies to the KIR Family of Potassium Channels

    The action of potassium (K+) channels is regulated by voltage,calcium and a variety of neurotransmitters. Each subfamily gener-ally consists of a primary pore-forming -subunit that is associat-ed with several regulatory subunits [1]. To date, 70 different genesthat encode the -subunits of K+ channels have been identified.The vast family of K+ channels has been subdivided into the threemain subfamilies: the 2 transmembrane (TM), 4 TM and 6 TM K+

    channels [2].

    Inwardly rectifying potassium (KIR) channels belong to the 2 TMfamily. They form a diverse family with seven main subtypes foundto date. They have two main physiological roles, to mediate trans-port across the cell membrane and to stabilize the restingmembrane potential near the K+ equilibrium potential. KIR 2 typechannels are partially responsible for controlling excitability of cells

    within the heart and brain, while KIR 6 type channels are impor-tant in the regulation of insulin secretion, the response to cardiacischemia and the control of vascular smooth muscle tone [3].

    The voltage-gated K+ (Kv) channels belong to the 6 TM family ofK+ channels. The KCNQ family of voltage-gated K+ channelsincludes five known members referred to as KV7.1 - KV7.5(KCNQ1 to KCNQ5) [4]. The KCNQ1 channel is important incardiac function. Mutations on KCNQ1 can be responsible forlong QT syndrome, a cardiac disorder that causes arrhythmias andsudden death [5]. KCNQ2/KCNQ3 heteromultimers are believed tobe the molecular correlates of the so-called M current [6].Mutations in either gene are associated with a form of epilepsyknown as benign familial neonatal convulsions [5].

    Anti-Potassium Channel KIR2.2, Prod. Code P 4496Anti-Potassium Channel KIR2.2 is developed in rabbit using apeptide corresponding to amino acid residues 391-409 of ratKIR2.2 as immunogen. The epitope is conserved in mouse andhuman. Anti-Potassium Channel KIR2.2 specifically recognizes thePotassium Channel KIR2.2 protein in rat brain and kidney mem-branes by immunoblotting.

    Anti-Potassium Channel KIR6.2, Prod. Code P 4621Anti-Potassium Channel KIR6.2 is developed in rabbit using apeptide corresponding to amino acid residues 372-385 of ratKIR6.2 as immunogen. The epitope is highly conserved in mouseand human. Anti-Potassium Channel KIR6.2 specifically recognizesthe Potassium Channel KIR6.2 protein in rat pancreas membranesby immunoblotting, and does not cross react with KIR6.1.

    Antibodies to the KCNQ Family of Voltage-Gated Potassium Channels

    Anti-Potassium Channel KV7.1 (KCNQ1), Prod. Code P 5372Anti-Potassium Channel KV7.1 (KCNQ1) is developed in rabbitusing a peptide corresponding to amino acid residues 661-676 ofhuman KCNQ1 as immunogen. This sequence has 14/16 residuesidentical in rat and mouse. Anti-Potassium Channel KV7.1 specifi-cally recognizes the Potassium Channel KV7.1 protein in rat heartmembranes by immunoblotting.

    Anti-Potassium Channel KCNQ2 (KV7.2, Voltage-gatedPotassium Channel QKT Subfamily Member 2), Prod. Code P 4371 Anti-Potassium Channel KCNQ2 (KV7.2) is developed inrabbit using a peptide corresponding to amino acid residues 578-593 of rat KCNQ2 as immunogen. The epitope is highly conservedin human. Anti-Potassium Channel KCNQ2 specifically recognizesKCNQ2 protein in KCNQ2 transfected HEK-293 cells byimmunoblotting. It does not cross react with KCNQ3 or other QKTproteins. There are at least nine recognized splice variants of ratKCNQ2. This antibody recognizes all except splice variants B and G.

    Anti-Potassium Channel KCNQ3 (KV7.3, Voltage-gatedPotassium Channel QKT Subfamily Member 3), Prod. Code P 5121Anti-Potassium Channel KCNQ3 (KV7.3) is developed in rabbitusing a peptide corresponding to amino acid residues 668-686 ofrat KCNQ3. The epitope is highly conserved in mouse and human.Anti-Potassium Channel KCNQ3 specifically recognizes KCNQ3protein in rat brain and may be used for the detection ofPotassium Channel KCNQ3 by immunoblotting and immunohisto-chemistry.References1. Alexander, S.P., et al., Guide to receptors and channels, 1st edition., Br. J.

    Pharmacol., 141, Suppl 1:S1-S126 (2004).2. Gutman, G.A., et al., International Union of Pharmacology. XLI. Compendium

    of voltage-gated ion channels: potassium channels., Pharmacol. Rev., 55, 583-586 (2003).

    3. Ashcroft, F.M., ed, Ion Channels and Disease, Academic Press, 2000.4. Robbins, J., KCNQ potassium channels: physiology, pathophysiology, and

    pharmacology., Pharmacol. Ther., 90, 1-19 (2001).5. Hubner, C.A. and Jentsch, T.J., Ion channel diseases., Hum. Mol. Genet., 11,

    2435-2345 (2002).6. Wang, H.S., et al., KCNQ2 and KCNQ3 potassium channel subunits: molecular

    correlates of the M-channel., Science, 282, 1890-1893 (1998).

    Explore our NEW Antibody Guide!

    Over 250 pages Over 3,000 quality antibodies all rigorously

    tested Hundreds of NEW antibodies Organized by area of study for easy reference World-renowned technical service Timely delivery anywhere

    Fill out and return the enclosed Business ReplyCard to receive your Guide: Antibodies, Toolsfor Life Science Research!

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    SR 12813: PXR agonist and HMG-CoAreductase inhibitor

    The pregnane X receptor (PXR), amember of the nuclear receptor fami-ly of ligand-activated transcriptionfactors, is a transcriptional regulatorof multiple cytochrome P450 andmultidrug resistance-associated pro-teins. SR12813 activates both humanand rabbit PXR [1,2]. SR12813

    inhibits cholesterol synthesis by reducing cellular HMG-CoAreductase activity, displaying an IC50 value of 0.85 M [3].

    References1. Jones, S., et al., The pregnane X receptor: a promiscuous xenobiotic receptor

    that has diverged during evolution., Mol. Endocrinol., 14, 27-39 (2000).2. Watkins, R.E., et al., The human nuclear xenobiotic receptor PXR: structural

    determinants of directed promiscuity., Science, 292, 2329-2333 (2001).3. Berkhout, T.A., et al., The novel cholesterol-lowering drug SR-12813 inhibits

    cholesterol synthesis via an increased degradation of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase., J. Biol. Chem., 271, 14376-14382 (1996). YM-53601: Squalene synthase inhibitor

    Squalene synthase is an enzymevital for cholesterol biosynthesis.YM-53601, a squalene synthaseinhibitor, lowered not only plasmacholesterol, but also plasma triglyc-eride levels. YM-53601 equallyinhibited squalene synthase func-

    tion in hepatic microsomes prepared from several animal speciesand suppressed cholesterol biosynthesis in rats (ED50 32 mg/kg).In rhesus monkeys, when dosed at 50 mg/kg twice daily for 21 days, YM-53601 decreased plasma non-HDL-C (high densitylipoprotein cholesterol) by 37%, whereas the HMG-CoA reduc-tase inhibitor, pravastatin, when dosed at 25 mg/kg twice dailyfor 28 days, failed to do so.

    Reference1. Ugawa, T., et al., YM-53601, a novel squalene synthase inhibitor, reduces

    plasma cholesterol and triglyceride levels in several animal species., Br. J.Pharmacol., 131, 63-70 (2000).

    sPLA2 inhibitor Available First from Sigma-RBI

    Orally active, potentsecretory PhospholipaseA2 (sPLA2; Group IIa)inhibitor - IC50 = 29 nMagainst human recombi-nant nonpancreatic sPLA2.

    References1. Arumugam, T.V., et al., Comparative protection against rat intestinal reper-

    fusion injury by a new inhibitor of sPLA2, COX-1 and COX-2 selectiveinhibitors, and an LTC4 receptor antagonist., Br. J. Pharmacol., 140, 71-80(2003).

    2. Hansford, K.A., et al., D-Tyrosine as a chiral precusor to potent inhibitors ofhuman nonpancreatic secretory phospholipase A2 (IIa) with anti-inflamma-tory activity., Chembiochem., 4, 181-185 (2003).

    O

    CO2H

    HN

    O

    Prod. Code Y 0128

    Prod. Code S 3319

    Exo 1: Reversible inhibitor of exocytosis

    Exo 1 [2-(4-fluorobenzoylamino)benzoic acidmethyl ester] is a cell-permeable methylan-thranilate analog that reversibly inhibitsvesicular traffic from the ER (endoplasmicreticulum) to Golgi in mammalian cells. It is aselective and potent modifier of Golgi ADP-ribosylation factor (ARF) 1 GTPase activityand has no effect on other endocytic

    organelles such as endosomes and trans-Golgi network (TGN).Exo 1 inhibits exocytosis displaying an IC50 value of 20 M. [1].

    Reference1. Feng, Y., et al., Exo1: a new chemical inhibitor of the exocytic pathway.

    Proc. Natl. Acad. Sci. USA, 100, 6469-6474 (2003).

    NH

    O

    F

    N

    HCl

    Prod. Code S 4194

    Prod. Code E 8280

    HO

    P(O)(OC2H5)2

    P(O)(OC2H5)2H3C

    H3CH3C

    CH3

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    COOCH3

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    DAPT (LY-374973): -secretase inhibitor

    HN

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    COO-t-Bu

    Ph

    Alzheimers disease (AD)accounts for the majority of thedementia diagnosed over theage of 60 and represents thelargest unmet medical need inneurology with over 12 millionsufferers worldwide. The

    pathogenesis of AD is believed to result from the progressiveaccumulation in the brain of -amyloid (A), a 4 kDa protein. Aoriginates from the proteolytic cleavage of amyloid precursorprotein (APP) by -secretase followed by -secretase cleavage [1].Because inhibition of -secretase blocks the production of A,the identification of compounds that block the activity of thisenzyme has become a major focus of AD research.

    Sigma-RBI is pleased to offer DAPT, a -secretase inhibitor. DAPTinhibits -secretase in cultured cells, thus reducing A levels. Intransgenic mice, which develop amyloid plaques due to the over-expression of mutant APP, DAPT dose-dependently (10, 30, 100mg/kg, sc) reduces the A burden within 3 hr post administrationand maintains reduced levels 18 hr after treatment [2]. In addi-tion, DAPT causes Notch phenotyping in zebrafish embryos andDrosophila due to the inhibition of Notch intracellular domaingeneration, which is involved in gene transcription regulation,processing, translocation and signaling [3,4].

    References1. Lammich, S., et al., Presenilin-dependent intramembrane proteolysis of

    CD44 leads to the liberation of its intracellular domain and the secretion ofan Abeta-like peptide., J. Biol. Chem., 277, 44754-44759 (2002).

    2. Dovey, H.F., et al., Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain., J. Neurochem., 76, 173-181 (2001).

    3. Micchelli, C.A., et al., Gamma-secretase/presenilin inhibitors for Alzheimer'sdisease phenocopy Notch mutations in Drosophila., FASEB J. 17, 79-81 (2003).

    4. Sastre, M., et al., Presenilin-dependent gamma-secretase processing ofbeta-amyloid precursor protein at a site corresponding to the S3 cleavageof Notch., EMBO Rep., 2, 835-841 (2001).

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    Name Description Prod. Code

    L-685,458 Potent, selective, structurally novel -secretase L 1790inhibitor; equipotent in inhibition of both A1-42 and A1-40 peptide fragment production

    Prod. Code D 5942

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    APOPTOSIS AND CELL CYCLE

    D 5817 DMXAAApoptosis inducer; anti-vascular.

    E 8405 EB-47Potent inhibitor of PARP.

    I 1159 trans-4-Iodo-4'-boranyl-chalconeMDM2 inhibitor; immunomodulator.

    M 5318 MC2p

    M 5443 NLS-MC2p

    R 3528 Anti-phospho-Rb [pThr356] (rabbit)

    R 3403 Anti-phospho-Rb [pSer249/pThr252] (rabbit)

    R 3278 Anti-phospho-Rb [pSer612] (rabbit)

    R 4028 Anti-phospho-Rb [pSer780] (rabbit)

    R 3778 Anti-phospho-Rb [pSer807] (rabbit)

    R 3903 Anti-phospho-Rb [Ser807/pSer811] (rabbit)

    R 4278 Anti-phospho-Rb [pSer811] (rabbit)

    R 4153 Anti-phospho-Rb [pThr821] (rabbit)

    R 4403 Anti-phospho-Rb [pThr826] (rabbit)

    T 2825 TIQ-APotent inhibitor of PARP; anti-apoptotic.

    ASSAY KITS

    CS0400 Casein kinase assay kit

    CS0340 Dihydrofolate reductase (DHFR) assay kit

    CS0260 Glutathione assay kit

    CS0410 Glutathione S-transferase (GST) assay kit

    CS0380 JNK activity assay kit

    CS0250 p38 MAPK activity assay kit

    CS0390 Mitochondria staining kit

    CS0430 Tau Elisa, mouse

    CS0440 Phospho-Tau [pSer199] Elisa, mouse

    CS0170 Thioredoxin reductase assay kit

    CYTOKINES, GROWTH FACTORS AND HORMONES

    A 9853 Anti-Androgen Receptor (rabbit)

    C 3866 Anti-Calcitonin Receptor-Like Receptor (rabbit)

    M 7068 MPP dihyrochlorideSpecific ER estrogen receptor antagonist.

    P 9121 Prolactin Receptor Fc Chimerahuman, recombinant, expressed in NSO cells

    V 5014 Anti-phospho-VEGFR2 [pTyr1054/pTyr1059] (rabbit)

    V 5239 Anti-phospho-VEGFR2 [pTyr951] (rabbit)

    V 5264 Anti-phospho-VEGFR2 [pTyr1214] (rabbit)

    V 5389 Anti-phospho-VEGFR2 [pTyr1054] (rabbit)

    CYTOSKELETON AND EXTRACELLULAR MATRIX

    A 3854 Monoclonal Anti--Actin-PeroxidaseClone AC-15 (mouse)

    C 5615 Monoclonal Anti-phospho -Catenin [pSer45]Clone BCS-45 (mouse)

    C 0864 Anti-phospho-Cortactin [pTyr466], mouse (rabbit)

    C 0739 Anti-phospho-Cortactin [pTyr421], mouse (rabbit)

    G 8419 GW311616APotent, intracellular human neutrophil elastase inhibitor.Sold for research purposes under agreement fromGlaxoSmithKline.

    H 4663 HMBAInhibitor of microtubule polymerization; apoptosis inducer.

    P 8996 Monoclonal Anti-Pinch-1, Clone PINCH-C58 (mouse)

    P 0372 Anti-Podocin (rabbit)

    P 7496 Anti-Protein Disulfide Isomerase (PDI) (rabbit)

    R 3653 Anti-Radixin (rabbit)

    T 1450 Anti--Tubulin (LL-17) (rabbit)

    T 0950 Anti--Tubulin (QG-17) (rabbit)

    T 2200 Anti- III Tubulin (rabbit)

    V 4139 Anti-Vinculin (rabbit)

    V 4889 Anti-phospho-Vinculin [pTyr822] (rabbit)

    G PROTEINS AND CYCLIC NUCLEOTIDES

    B 4560 6-Bnz-cAMPMembrane permeable and selective cAMP-dependentprotein kinase (PKA) activator.

    A 2104 8-AHA-cAMPSelective cAMP-dependent protein kinase (PKA) activator.

    C 8990 Sp-8-pCPT-cAMPSelective cAMP-dependent protein kinase (PKA) activator.

    F 9553 FTI-276Highly potent Ras CAAX peptidomimetic, antagonizes Hand K-Ras oncogenic signaling; inhibitor of farnesyl-transferase (FTase) in vitro.

    F 9803 FTI-277Highly potent Ras CAAX peptidomimetic; inhibitor offarnesyltransferase.

    G 5169 GGTI-298CAAX peptidomimetic; inhibitor of geranylgeranyl-transferase I (GGTase).

    G 5294 GGTI-2133CAAX peptidomimetic; inhibitor of geranylgeranyl-transferase I (GGTase I).

    G 2420 Anti-G Protein-Coupled Receptor BG37/TGR5 (rabbit)

    G 2670 Anti-G Protein-Coupled Receptor AGR9 (rabbit)

    I 8283 ICI 63197Phosphodiesterase IV (PDE IV) inhibitor.

    P 0747 8-MA-cAMPSelective cAMP-dependent protein kinase (PKA) activator.

    P 0622 PET-cGMPcGMP-dependent protein kinase (PKG I and PKG II) activator.

    P 0872 8-PIP-cAMPSelective cAMP-dependent protein kinase (PKA) activator.

    S 6069 Sp-5,6-DCI-cBIMPSSelective cAMP-dependent protein kinase (PKA) activator.

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    GENE REGULATION AND EXPRESSION

    D 5817 DMXAAApoptosis inducer; anti-vascular.

    A 8103 Monoclonal Anti-hABH1, Clone HABH1-151 (mouse)

    A 8228 Monoclonal Anti-hABH2, Clone HABH2-7 (mouse)

    A 8353 Monoclonal Anti-hABH3, Clone HABH3-99 (mouse)

    A 8853 Anti-phospho-ATF2 [pThr71] (rabbit)

    B 3810 Anti-BRCA1-Associated Protein BRAP2 (rabbit)

    C 6240 CITCOConstitutive adrostane receptor (CAR) agonist; nuclearreceptor NR113 agonist.

    D 4567 Anti-DNMT1 (rabbit)

    F 1054 Anti-FOXC2 (rabbit)

    G 8794 Anti-GATA4 (rabbit)

    G 8669 Anti-GATA5 (rabbit)

    G 6669 Monoclonal Anti-Gemin 2, Clone 2E17 (mouse)

    G 6544 Monoclonal Anti-Gemin 3, Clone 12H12 (mouse)

    H 4788 Anti-HES-2 (rabbit)

    H 5038 Anti-HES-3 (rabbit)

    H 4913 Anti-HEX (rabbit)

    I 8158 Anti-Irx2a (rabbit)

    H 4538 Monoclonal Anti-Histone Deacetylase 5 (HDAC5)Clone HDAC5-35 (mouse)

    I 9283 ITEEndogenous ligand identified for aryl hydrocarbon receptor; ligand inducible transcription factor.

    L 5042 Anti-LHX4 (rabbit)

    L 5167 Anti-LIG4 (rabbit)

    M 6818 Monoclonal Anti-MeCP2, Clone Mec-168 (mouse)

    G 6919 Anti-G9a Methyltransferase (rabbit)

    M 6193 Anti-MRE11A (rabbit)

    M 5943 Anti-Mtsh1/teashirt (rabbit)

    N 8411 Anti-NeuroD2 (rabbit)

    N 8286 Anti-NSCL 2 (HEN2) (rabbit)

    P 6246 Monoclonal Anti-PABP, Clone 10E10 (mouse)

    P 8872 Anti-PACAP Receptor Type 1 (rabbit)

    P 6746 Monoclonal Anti-PML, Clone PML-97 (mouse)

    P 6871 Anti-PRMT1 (NQ-15) (rabbit)

    P 6996 Anti-PRMT1 (TK-16) (rabbit)

    P 7497 Anti-Prostate-Specific G Protein-Coupled Receptor(PSGR) (rabbit)

    R 6153 Monoclonal Anti-RhoE, Clone 4 (mouse)

    R 4528 Monoclonal Anti-hnRNP-A1, Clone 9H10 ( mouse)

    R 4653 Monoclonal Anti-hnRNP-A2/B1, Clone DP3B3 (mouse)

    R 5028 Monoclonal Anti-hnRNP-C1/C2, Clone 4F4 (mouse)

    R 4903 Monoclonal Anti-hnRNP-L, Clone 4D11 (mouse)

    R 5653 Monoclonal Anti-hnRNP-Q, Clone 18E4 (mouse)

    S 4319 Anti-Scratch (rabbit)

    S 1444 Anti-Sprouty 2 (N-terminal) (rabbit)

    S 1819 Anti-Sprouty 2 (C-terminal) (rabbit)

    GENE REGULATION AND EXPRESSION (continued)

    S 4194 SR 12813PXR (NR 112) agonist; cholesterol lowering drug; HMGCoA reductase inhibitor.

    U 4758 Monoclonal Anti-U2AF65, Clone MC3 (mouse)

    Z 4775 ZebularineCytidine analog; cytidine deaminase inhibitor; DNA demethylating agent.

    IMMUNE CELL SIGNALING AND BLOOD

    A 1854 ()-ArctigeninDibenzylbutyrolactone ligand; natural product; viralintegrase and topoisomerase II inhibitor; antioxidant;antiviral; anti-inflammatory and immunomodulator.

    B 3685 Monoclonal Anti-BOB78, Clone BOB78 (mouse)

    P 8747 Anti-Proteinase-Activated Receptor 2 (rabbit)

    T 5700 Anti-Thrombin Receptor (rabbit)

    INTRACELLULAR CALCIUM SIGNALING

    C 4491 Anti-Calcium-Sensing Receptor CASR (rabbit)

    ION CHANNELS

    A 6603 Aa1, recombinant, expressed in E. coliBlocks Shaker B channels expressed in Xenopus oocytes;blocks fast (A-type) K+ currents in cerebellar granular cells.

    C 2240 Anti-Calcium Channel CaV3.1 (1G) (rabbit)

    C 2615 Chromanol 293BSlow delayed rectifier K+ current blocker acting viaKCNQ1 channels.

    H 3038 Anti-HCN1 (rabbit)

    I 6783 Isopimaric acidPotent opener of large conductance Ca2+-activated K+

    (BK) channels.

    K 0514 Monoclonal Anti-KCNK9 (TASK3), Clone KCN-75 (mouse)

    M 3318 Anti-MiRP1 (rabbit)

    N 7286 Anti-NHERF-1 (rabbit)

    N 8161 NS309Ca2+-activated IK/SK K+ channel activator.

    P 4996 Anti-Potassium Channel EAG-2 (rabbit)

    P 4371 Anti-Potassium Channel KCNQ2 (rabbit)

    P 5121 Anti-Potassium Channel KCNQ3 (rabbit)

    P 4496 Anti-Potassium Channel Kir2.2 (rabbit)

    P 4621 Anti-Potassium Channel Kir6.2 (rabbit)

    S 6444 N-SalicyloyltryptamineCa2+-activated K+ channel activator; anticonvulsant;neuroprotectant.

    New Products for Cell Signaling & Neuroscience

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    ION CHANNELS (continued)

    S 0944 Slotoxin, recombinant, expressed in E. coliBlocks Maxi K+ channels.

    S 0819 Anti-Sodium Channel NaV1.5 (rabbit)

    T 0325 Anti-TRPC5 (rabbit)

    LIPID SIGNALING

    A 9978 AICARAMP-activated protein kinase (AMPK) activator.

    C 4615 CloricromeneAnti-thrombotic coumarin derivative; produces coronarydilation; stimulates prostacyclins and lowers TXB2synthesis in platelets.

    C 9115 CP-24879Delta5/Delta6 (5/6) desaturase inhibitor.

    F 1179 FPL-55712LTD4 Leukotriene receptor antagonist.

    H 4413 HydroxyfasudilRho-Kinase Inhibitor.

    K 0639 Ki16425Subtype-selective, potent and reversible LPA1 and LPA3receptor antagonist.

    M 5693 MEDICA 16ATP-citrate lyase inhibitor; potent triacylglycerol-loweringagent.

    M 8192 15R-Methyl-prostaglandin D2Potent and selective DP2 prostanoid receptor agonist.

    M 5818 Monoclonal Anti-hMps1, Clone N1 (mouse)

    S 3319 sPLA2 inhibitorOrally active, potent secretory phospholipase A2 (sPLA2;Group IIa) inhibitor.

    N 0912 NAEPASelective lysophosphatidic acid-1 (LPA1) receptor agonist;LPA mimetic.

    O 4139 OrlistatPancreatic lipase inhibitor.

    P 7622 Anti-Prostacyclin Receptor (rabbit)

    P 7872 Anti-DP Prostanoid Receptor (rabbit)

    P 7747 Anti-EP2 Prostanoid Receptor (rabbit)

    P 8372 Anti-EP3 Prostanoid Receptor (rabbit)

    P 8497 Anti-EP4 Prostanoid Receptor (rabbit)

    P 8622 Anti-Prostaglandin F2 Receptor (rabbit)

    S 4194 SR 12813PXR (NR 112) agonist; cholesterol lowering drug; HMGCoA reductase inhibitor.

    S 3944 SW2871Novel and selective human sphingosine-1-phosphate sub-type 1 (S1P1) receptor agonist.

    T 5200 Triparanol Desmosterol Delta24 (24) reductase inhibitor.

    NEUROBIOLOGY

    A 0479 AdrafinilWake-promoting agent; modafinil analog.

    A 9603 Anti-APH-1aL (rabbit)

    B 1935 S(+)-Butorphan mandelate/ opioid receptor agonist.

    D 5942 DAPT (LY-374973)-secretase inhibitor. Sold under license to US PatentNumbers 6,211,235 and 6,191,166.

    N 9161 Notch-2/Fc Chimerarat, recombinant, expressed in NSO cells

    N 9036 Notch-3/Fc Chimerahuman, recombinant, expressed in Sf 21 cells

    N 8911 Notch-3/Fc Chimeramouse, recombinant, expressed in insect cells

    P 9246 PB28 dihydrochlorideSelective 2 sigma receptor ligand; putative agonist.

    R 5403 Monoclonal Anti-Rhodopsin, Clone 1D4 (mouse)

    S 5067 -Secretase (BACE1), human, recombinant

    S 2944 Monoclonal Anti-SMN, Clone 2B1 (mouse)

    S 2069 Anti-SNAP29 (rabbit)

    S 2319 Anti-SNAP23 (DS-19) (rabbit)

    S 2194 Anti-SNAP23 (TS-19) (rabbit)

    S 4819 Anti-Syntaxin 7 (rabbit)

    V 4514 Anti-Vesicle Associated Membrane Protein 4,(VAMP4) (rabbit)

    NEUROTRANSMISSION

    A 3104 A-331440 L-tartaric acid saltNon-imidazole H3 histamine receptor antagonist. Subjectto US Patent Nos. 6,515,013 and 6,620,839. Sold underlicense from Abbott Laboratories.

    A 6853 2A-Adrenergic Receptor Preparation, human

    A 6728 1-Adrenergic Receptor Preparation, human

    C 4366 Anti-Cholecystokinin B Receptor (rabbit)

    C 6848 Ciproxifan maleatePotent, selective H3 histamine receptor antagonist.

    C 4740 Cisapride5-HT4 serotonin receptor agonist.

    C 4241 Anti-Corticotropin-Releasing Factor Receptor2(CRFR2) (rabbit)

    D 6317 DMeOBNegative allosteric modulator of mGluR5 metabotropicglutamate receptors.

    D 4067 Sleep-Inducing PeptideTrp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu

    D 2442 Anti-Dopamine Transporter (rabbit)

    E 7155 ETA Endothelin Receptor Preparation, human

    G 5544 Anti-GABAA Receptor (6 subunit) (rabbit)

    G 5669 Anti-GABAA Receptor (2 subunit) (rabbit)

    G 0170 Anti-GABAA Receptor (4 subunit), N-terminus (rabbit)

    New Products for Cell Signaling & Neuroscience

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    NEUROTRANSMISSION (continued)

    G 0295 Anti-GABAA Receptor (6 subunit), cytosolic loop(rabbit)

    G 9169 Anti-GABAA Receptor (4 subunit), cytosolic loop(rabbit)

    G 9294 Anti-GABAA Receptor (5 subunit), cytosolic loop(rabbit)

    G 9419 Anti-GABAA Receptor (1 subunit), cytosolic loop(rabbit)

    G 9544 Anti-GABAA Receptor (2 subunit), cytosolic loop(rabbit)

    G 9669 Anti-GABAA Receptor (3 subunit), cytosolic loop(rabbit)

    G 9794 Anti-GABAA Receptor ( subunit), N-terminus (rabbit)

    G 9919 Anti-GABAA Receptor (2 subunit), cytosolic loop(rabbit)

    G 4419 GalnonNon-peptide galanin receptor agonist.

    G 7919 Anti-Glutamate Receptor 4, Metabotropic (mGluR4)(rabbit)

    G 5419 Monoclonal Anti-Glutamic acid decarboxylase 67(GAD67), Clone K-87 (mouse)

    I 0909 6-IodonordihydrocapsaicinTRPV1 (V1) vanilloid receptor antagonist.

    I 7033 6'-Iodoresiniferatoxin (6-I-RTX)VR1 vanilloid receptor partial agonist.

    J 3770 JNJ7777120First potent, selective non-imidazole H4 histaminereceptor antagonist.

    K 0389 K41498CRF2 corticotropin releasing factor receptor antagonist(peptide); antisauvagine-30 analog.

    M 4068 Mesoridazine benzenesulfonateD2 dopamine receptor antagonist; antipsychotic.

    M 1818 Molindone hydrochlorideD2 dopamine receptor antagonist; MAO inhibitor.

    M 9693 Anti-M2 Muscarinic Acetylcholine Receptor (rabbit)

    M 9568 Anti-M3 Muscarinic Acetylcholine Receptor (rabbit)

    N 7161 Nogo-66(1-40) antagonist peptidePromotes axonal regeneration by blocking effects ofmyelin-derived axon outgrowth inhibitors such asNogo66 or CNS myelin. Sold under a non-exclusivelicense. For research purposes only, and not fordiagnostic or therapeutic use or for use in humans.

    O 5014 Anti-1 Opioid Receptor (OPRD1) (rabbit)

    O 5139 Anti-1 Opioid Receptor (OPRM1) (rabbit)

    P 1747 Anti-Phospho-Tyrosine Hydroxylase [Ser31] (rabbit)

    P 2247 Anti-Phospho-Tyrosine Hydroxylase [Ser19] (rabbit)

    P 1997 Anti-Phospho-Dynamin [Ser774] (rabbit)

    P 2122 Anti-Phospho-Dynamin [Ser778] (rabbit)

    P 4746 Anti-Purinergic Receptor P2X6 (rabbit)

    P 4871 Anti-Purinergic Receptor P2Y12 (rabbit)

    S 0694 Anti-Somatostatin Receptor Type 2 (rabbit)(lyophilized powder)

    NEUROTRANSMISSION (continued)

    S 2694 SB-408124OX1 orexin receptor antagonist. Sold for researchpurposes under agreement from GlaxoSmithKline.

    S 1069 (S)-SNAP 5114GAT-2 and GAT-3 GABA transporter inhibitor.

    S 1445 Anti-Somatostatin Receptor Type 1 (rabbit)

    S 0695 Anti-Somatostatin Receptor Type 2 (rabbit)

    S 0820 Anti-Somatostatin Receptor Type 3 (rabbit)

    S 0945 Anti-Somatostatin Receptor Type 4 (rabbit)

    S 1070 Anti-Somatostatin Receptor Type 5 (rabbit)

    T 0575 TopiramateKainate GluR5 glutamate receptor antagonist; anti-convulsant.

    T 5950 Anti-NK1 Tachykinin Receptor (rabbit)

    T 6075 Anti-NK2 Tachykinin Receptor (rabbit)

    T 5825 Anti-NK3 Tachykinin Receptor (rabbit)

    V 4264 VK-28Neuroprotectant; brain permeable iron chelator.

    NITRIC OXIDE AND CELL STRESS

    E 8655 Monoclonal Anti-E6AP, Clone E6AP-330 (mouse)

    H 4163 Anti-Heat Shock Factor 1 (HSF1) (rabbit)

    H 4038 Anti-Heat Shock Protein 40 (rabbit)

    S 5069 Anti-Superoxide Dismutase (MnSOD) (DD-17) (rabbit)

    S 5569 Anti-Superoxide Dismutase (MnSOD) (KC-19) (rabbit)

    PROTEIN PHOSPHORYLATION

    P 5997 Anti-Phospho-CAM Kinase II [pThr305] (rabbit)

    P 2372 Protein Kinase A, rat brain, purified

    R 2903 Anti-RALT/MIG-6 (SG-16) (rabbit)

    S 1819 Anti Sprouty-2 (C-terminal) (rabbit)

    S 1444 Anti Sprouty-2 (N-terminal) (rabbit)

    T 5575 TG003Potent, specific, reversible and ATP-competitive inhibitorof Cdc2-like kinase (Clk).

    T 2949 Anti-mTOR (FRAP) (rabbit)

    T 1325 Anti-phospho Tyrosine (rabbit)

    T 1575 Anti-phospho Tyrosine (pTyr256) (rabbit)

    V 4764 Anti-phospho-Vav1 [pTyr160] (rabbit)

    V 4639 Anti-phospho-Vav3 [pTyr173] (rabbit)

    Z 0151 Anti-phospho-ZAP-70 [pTyr292] (rabbit)

    Z 0276 Anti-phospho-ZAP-70 [pTyr315/pTyr319] (rabbit)

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