CHEM E-120 Harvard University Extension School Spring 2011

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1 CHEM E-120 Harvard University Extension School Spring 2011 Disorders of Mood and Behavior Anxiety Classical Benzodiazepines – GABA A Allosteric Modulators Partial Agonists Subtype Selective Benzodiazepines – α2/α3 5-HT 1A agonist 3/2/11 CHEM E-120

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CHEM E-120 Harvard University Extension School Spring 2011. Disorders of Mood and Behavior Anxiety Classical Benzodiazepines – GABA A Allosteric Modulators Partial Agonists Subtype Selective Benzodiazepines – α2/α3 5-HT 1A agonist. Anxiety. A normal response to threatening situations - PowerPoint PPT Presentation

Transcript of CHEM E-120 Harvard University Extension School Spring 2011

Page 1: CHEM E-120 Harvard University Extension School Spring 2011

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CHEM E-120Harvard University Extension School

Spring 2011

Disorders of Mood and BehaviorAnxiety

Classical Benzodiazepines – GABAA Allosteric Modulators

Partial AgonistsSubtype Selective Benzodiazepines – α2/α3

5-HT1A agonist

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Anxiety

A normal response to threatening situations

Key feature is increased fearfulness accompanied by subjective (heightened sense of awareness to a deep fear of impending disaster and death) and physiological manifestations.

Panic Disorder (DSM-IV 300.01)Post-traumatic stress disorder (PTSD, DSM-IV 309.81)Generalized Anxiety Disorder (GAD, DSM-IV 300.02)Social phobia (DSM-IV 300.23)Obsessive-compulsive disorder (OCD, DSM-IV 300.3)

Anxiety and depression often occur together (comorbidity)e.g. 50% of patients with panic attacks have depression

Most common of psychiatric disorders, 10-30% of population

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Neurobiology of Anxiety

Animal models of fear and avoidance1

Fear network has been proposed centered on the amyglada2

1. Animal Models of Anxiety… Trends in Pharmacological Sciences 2008, 29, 4932. Neuroanatomical Hypothesis of Panic Disorder, American J. Psychiatry 2000, 157, 493

Sensory thalamus cortex

amyglada

HypothalamusHPA axis Locus cerules

NE, CRH

periaqueductal gray region axisautonomic response (fight or flight)

hippocampusmemory, learning

dopaminergicnoradrenergicserotonergiccholinergic

Main Neurotransmitters are GABA (inhibitory) and Glutamic Acid (excitory)

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Therapeutic Targets – Approved AnxiolyticsBenzodiazepines

Allosteric modulators of GABAA ligand-gated Cl- ion channel where they increase the influx of Cl-, leading to hyperpolarization – reduction in neuronal activity

Allosteric modulation – a drug binds to a different site on a protein than where GABA binds, changing the conformation of the ion channel, increasing the affinity of GABA. Positive Cooperativity.

Alprazolam (Xanax) Panic Disorder, Social PhobiaChlordiazepoxide (Librium) AnxietyClonazepam (Klonopin) GAD, Panic Disorder, Social PhobiaDiazepam (Valium) Anxiety

Side effects

Sedation, dose-related transition anxiolytic sedativeAddiction – mildMemory impairment - Rohypnol (flunitrazepam) date rape

Lyrica (Pfizer) not approved for GAD

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Benzodiazepines

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GABAA Ion Channels

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Ion channel is pentameric structure where each pentamer subunit is composed of four polypeptides, 19 subtypes.

Known the benzodiazepines (BZ) bind to sites on the interface of and subunits. GABA binds to 2 sites on subunits.

Currently thought that the BZ binding site involves a combination of 1, 2, 3 or 5 + 2 or 3.

1 thought to play a role in amnesia and sedative effects of BZ21 and 32 thought to be most important for anxiolytic effects of BZ5 memory component?

Barbiturates and alcohol also bind to GABAA

Zolpidem (Ambien) binds to GABAA

1 Science 2000, 290(5489)131 (transgenic mice)2 Journal of Neuroscience 2005, 25(460 10682

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Approved Nonbenzodiazepine Anxiolytics

Sertonergic System

SSRI’sSertraline (Zoloft) Panic disorder, OCD, PTSD, social phobiaFluoxetine (Prozac) OCD

5-HT1A agonistBuspirone (BuSpar) GAD

Noradrenergic System

Yohimbine blocks α2 adrenergic autoreceptors (activation inhibits noradrenergic neuronal activity) activating noradrenergic activity – induces panic attacks

NSRIVenlafaxine (Effexor) GAD

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GABAA – Benzodiazepines (BZ)

Benzodiazepines first discovered in 1957, found to have potent anxiolytic activity in animal models of sedation. No binding assays, went directly from flask into animal models

inclined screen – muscle relaxation & sedationfoot shock induced aggression in mice and rats – taming effectcat – muscle relaxationpentylenetetrazole – sedation & anticonvulsant

Later found to bind to the GABAA Cl- ion channelallosteric binding increases binding affinity of GABA

Librium

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BZ potentiate Cl- influx

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GABA invokes 0.9 nA current response

Addition of BZ triples amplitude

Chemicals delivered to cultured mouse spinal cord neuronvoltage-clamped at -70 mV with amicroelectrode.

CRC Press GABA and benzodiazepine Receptors Vol 1 1988

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Benzodiazepine PotenciesCorrelation between receptor affinity and behavioral potency among various benzodiazepines. Benzodiazepines were tested for their potency (Ki) in displacing [3H]diazepam from specific BDZ binding sites on rat cerebral cortical membranes. The resulting values were highly correlated (r=.90, p<.0001) with the behavioral potency of the same drugs (EDmin) in the cat muscle relaxant test.

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Benzodiazepine SAR

- stackingvan der waalsC7 electronegativegroup tends inc funcanxiolytic activity

HBA critical

C3 substitution decreasesantagonist activity but not agonist activity

tolerant of substituents

Not required for in vitro bindingbut is for in vivo efficacy4’ very sensitive to substitution

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Synthesis of Benzodiazepines

2-aminoaryl ketones

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PharmacophoreThose parts of the drug molecule that interact with the protein: key interactions that are responsible for the biological activity of the drug.

Medicinal Chemists commonly refer to the pharmacophore as consisting of

a scaffold (core)pendant functional groups bioactive conformation (i.e. the sterochemistry).

A pharmacophore does not necessarily represent a real molecule.

dab

dbc

dcd

dad

dac

a

b c

d

abcbcdetc

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Ligand-based Drug Design

In structure-based computerized drug design, the 3D structure of theTarget and drug should be known with a high degree of resolution.

The exact 3D structure of most receptors is not know.

1. Series of assayed ligands2. Generate energy-minimized structures – molecular mechanics3. Calculate various properties - descriptors4. Determine if a common set of shape or descriptors describe

the ensemble - pharmacophore

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Theoretical MethodsMolecular Mechanics

Treats atoms as balls and bonds as springs - classical mechanicsAssigns x,y,z coordinates to atoms in a molecule and calculates the potential energy at positionsForce Field: collection of values that define the change in energy with geometryForce fields can be transferred from one molecule to another to predict geometry.

calculate the potential energy of a conformation

Methods: MM1, MM2, AMBER, OPLS

Quantum Mechanics

Represents molecules in terms of their electron distributionThe shapes of orbitals (sp3, sp2, sp, π) and the electron distribution derive from QM.

partial atomic charges (areas of high and low electron density)electrostatic potentialdipole moments (polar bonds)

Methods: MINDO, ZINDO, PM3

QSAR (Quantitative Structure Activity Relationships) combine aspects of bothsize & charge

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Descriptors of Molecules

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Generating the Pharmacophore

Usually some type of iterative process where a compound(s) a modelIs developed. A training set of compounds is overlayed and the fitquantified by a scoring function. This is used to predict the biological activity (K i) for a set of compounds and compared to the known values.

The model is then adjusted as needed.

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Intermolecular Bonding

Hydrophobic Pocket

Salt bridge3/2/11 18CHEM E-120

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Benzodiazepine Binding Models

Relative locations of the descriptors and regions of the unified pharmacophore/ receptor model. The pyrazolo[3,4-c] quinolin-3-one CGS- 9896 (dotted line), a diazadiindole (thin line), and diazepam (thick line) aligned within the unified pharmacophore/receptor model for the Bz BS.

H1 and H2 represent hydrogen bond donor sites within the Bz BS

A2 represents a hydrogen bond acceptor site necessary for potent inverse agonist activity in vivo.

L1, L2, L3 and LDi are four lipophilic regions

S1, S2, and S3 are regions of negative steric repulsion.

LP = lone pair of electrons on the ligands

Current Medicinal Chemistry, 2007, 14, 2755-2775

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Benzodiazepine Binding Models

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Benzodiazepine Binding Models

Current Med Chem 2007, 14, 27553/2/11 CHEM E-120

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Receptors/Drugs - Partial Agonists

epartial agonist = [A]2

[A]1

Emax of partial agonist

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Alprazolam (Xanax)

This type of modification is leading intonew nonbenzodiazepines that bind selectivelyto the 2 site and/or are partial agonists

BZ use is limited by side effects, e.g., sedation and amnesia, the development of tolerance, and concerns about dependence and withdrawal. These side effects are a natural extension of their mechanism of action. Considerable effort has been expended over the past three decades to discover and develop novel, anxioselective BZ ligands that have improved side effect profiles. (Comprehensive Medicinal Chemistry II Chapter 6.04)

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New Approaches towards GABAA - Partial Agonists

Clinical trialsfor GAD andpanic disorderbut sedative

No tolerance to anxiolytc effect, no withdraw, lower abuse potential

EC50 = 3-10 MSimilar to diazepamPhase III but livertoxicity

Low nM N

N

N

O

Ambien (Zolpidem)3/2/11 CHEM E-120

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New Approaches towards GABAA - Subtype Selective

Ki similar but no efficacy at 1

1,2,3 selective1,5 partial agonist2,3 full agonist

Low nM at 1,2,3,53 full agonist1,2,5 partial agonist

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2/3 selective example - Merck

Ki (nM) Efficacy (1.0)1 = 1.5 -7% (antagonist)2 0.123 = 8.5 0.445 = 12.1 0.01

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Serotonergic System in Anxiety

Agonists for 5-HT1A receptor presynaptic (autoreceptor) in raphe nuclei could contribute to delayed onset.

Buspirone (Buspar) is a 5-HT1A partial agonist approved for GAD. NonsedativeIneffective in patients who have previously taken benzodiazepines.Delayed onsetBuspirone has no significant affinity for benzodiazepine receptors and does not affect GABA binding in vitro or in vivo when tested in preclinical models.Buspirone has moderate affinity for brain D2-dopamine receptors. Some studies do suggest that buspirone may have indirect effects on other neurotransmitter systems.

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5-HT1A Selective Compound

J. Med. Chem 2001, 44, 186

Selectivity problems versus 1-anderergic receptorHigh homology (45%) in transmembrane amino acid sequences of 5-HT1A and 1-anderergic receptors

To design compounds with selectivity for 5-HT1A versus 1 synthesized a training set of 32 compounds based on the structure below. The structural field of compounds VI is defined with 6 parameters:

three indicator variables (IA, IB and In) size of the A and B rings and nlipophilic ()electronic σo- or σm- steric (MR)

Used to pick the R groups from a set of 387 substituents.

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5-HT1A Selective Compound

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5-HT1A Selective Compound

J. Med. Chem 2001, 44, 186, 198

n = 4m = 0,1

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5-HT1A Selective Compound

J. Med. Chem 2001, 44, 186, 198

Meta-position m-bromo or m-amino group (VW(Br) = 17.2 Å3; VW(NH2) = 11.4 Å3) leads to compounds with the same affinity at both receptors. A trifluoromethyl group (VW = 24.2 Å3) at this position leads to an increase in the 5-HT1A selectivity (compound 28: 26-fold).

Best selectivity ratio is reached with the most voluminous group, a m-NHCOPri (VW = 70.8 Å3) which leads to the most selective compounds 20 and 32 (98- and 59-fold, respectively).

n = 4 favors 5-HT1A

ring sizeno effect

ortho no effect

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5-HT1A Selective Antagonist

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QSAR

Pharmacology

No effect of mouse rectal tempBlocked hypothermia induced by 8-OH-DPAT (5-HT1A agonist)No affect on behavioral tests but blocked effects of 8-OH-DPAT

5-HT1A antagonistD2 antagonist

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5-HT1A Selective Antagonist

J. Med. Chem 2001, 44, 198

Developed a QSAR model based on Hansch Analysis and Neural Networks to design compounds with selectivity for 5-HT1A versus 1

Used the training set of 32 compounds. Each chemical structure defined with 9 descriptors:

three indicator variables (IA, IB and In) size of the A and B rings and nlipophilic (o and m)electronic [field (F) and resonance (R)] position and nature of R.steric van der Waals (Vo, Vm)

Hansch Analysis 5-HT1A pKi = 7.55 – 0.251IA – 0.762IN=3 + 1.73F – 0.0292Vo – 0.0193Vm + 1.26o

1 pKi = 7.68 – 0.272IB + 1.32F – 0.0306Vo – 0.0417Vm + 1.17o

lead to:

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5-HT1A Selective Agonist

5-HT1A Ki = 27 nM antagonist 1 > 1000 nM

5-HT1A Ki = 4.1 nM agonist 1 > 1000 nM

JMC 2005, 48, 2548

affect 1

5-HT1A more tolerant

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5-HT1A Selective Agonist

J. Med. Chem 2005, 48, 2548

(S)-9

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5-HT1A Selective Agonist

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5-HT1A Selective Agonist

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5-HT1A Selective Agonist

Ionic piperizine N - Asp

H-bonds Thr, Ser, Trp

Van der waalsaromatic-aromaticTrp and Phe

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Future Targets

Transient Receptor Potential Channel 5 (TRPC5) mice in which TRPC5 gene was deleted showed diminished fear levels in anxiety models. Highly expressed in amygdalaCell. 2009 May 15;137(4):761-72

CRF1 antagonists – shown to produce anxiolytic effects

Neurokinin-2 (NK2) antagonist – Saredutant (SR48968) in Phase 3 trials for GAD. Less side effects than SSRI’s but relapse not significantly reduced (MDD)

Metabotropic (GPCR) glutamate receptors – mGlu 2 agonists, mGlu 1 antagonists

beta 3 receptor agonist – given after trauma, reduce memory of traumatic events (PTSD)

V1b receptor antagonist – vasopression peptide in HPA, found in amygdala

NK3 – NK2 receptor antagonist

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