Chemistry & Pharmacology of Sedative-Hypnotics & Pharmacology of Sedative-Hypnotics ... o SAR:...
2
Chemistry & Pharmacology of Sedative-Hypnotics Sedative Hypnotic Calming: ↓activity, ↓excitement Induce & facilitate sleep GABA A receptor BZD α1 sedation, anticonvulsant, anterograde amnesia BZD α2 anxiolysis Barbiturates ↑Cl - channel opening in GABA A receptor sedation Benzodiazepines Short-acting: triazolam Intermediate-acting: temazepam, estazolam Long-acting: quazepam, flurazepam Lead compound: triazolopyridazine (TZP), which is a ω1 BZD agonist Triazolam (Halcion) o Triazolam → active metabolite inactive glucuronides inactive carboxylic acide metabolites o Overdose: dose ≥ 0.5 mg bizarre, dangerous behavior o Max dose: 0.25 mg o Rebound anxiety o SAR: methyl group at triazolo ring allows for active metabolite Without methyl group there, will be major inactive metabolite, as in the case of estazolam Nomenclature o ω refers to receptor types o α refers to subunit subsites BZD receptor subtypes o BZD ω1 | high TZP affinity | hypnotic effect | throughout CNS, primarily cerebellar neurons o BZD ω2 | low TZP affinity | anxiolytic effect | hippocampus, striatum, spinal cord o BZD ω3 | low TZP affinity | sensory motor info processing | cerebellar granule cells Selective ω1 receptor agonists (non-BZD) Zolpidem, zaleplon, eszopiclone Characteristics: lipophilic, fast onset of action, short duration of action, little dependence/tolerance/withdraw symptoms, potentiated by ethanol Zolpidem (Ambien) o Zolpidem’s -CH 3 → inactive metabolites’ -CH 2 OH inactive metabolite’s –COOH Zaleplon (Sonata) o Zaleplon’s -CH 3 unstable → (dealkylated) inactive metabolite’s –H minor metabolite’s =O and –H o Zaleplon’s -CH 3 unstable → inactive metabolite’s =O minor metabolite’s =O and –H Eszopiclone (Lunesta) o Eszopiclone → (demethylation) –NH o Eszopiclone → (oxidation) –NO Barbiturates Metabolism o Hydroxylation (oxidation) inactive metabolite o N-dealkylation active metabolite o Aromatic hydroxylation o Desulfuration
Transcript of Chemistry & Pharmacology of Sedative-Hypnotics & Pharmacology of Sedative-Hypnotics ... o SAR:...
Chemistry & Pharmacology of Sedative-Hypnotics
Sedative Hypnotic
Calming: ↓activity, ↓excitement Induce & facilitate sleep
GABAA receptor
BZD α1 sedation, anticonvulsant, anterograde amnesia
BZD α2 anxiolysis
Barbiturates ↑Cl- channel opening in GABAA receptor sedation Benzodiazepines
Short-acting: triazolam
Intermediate-acting: temazepam, estazolam
Long-acting: quazepam, flurazepam
Lead compound: triazolopyridazine (TZP), which is a ω1 BZD agonist
Triazolam (Halcion)
o Triazolam → active metabolite inactive glucuronides inactive carboxylic acide metabolites
o Overdose: dose ≥ 0.5 mg bizarre, dangerous behavior o Max dose: 0.25 mg o Rebound anxiety o SAR: methyl group at triazolo ring allows for active metabolite
Without methyl group there, will be major inactive metabolite, as in the case of estazolam
Nomenclature o ω refers to receptor types o α refers to subunit subsites
BZD receptor subtypes o BZD ω1 | high TZP affinity | hypnotic effect | throughout CNS, primarily cerebellar neurons o BZD ω2 | low TZP affinity | anxiolytic effect | hippocampus, striatum, spinal cord o BZD ω3 | low TZP affinity | sensory motor info processing | cerebellar granule cells
Selective ω1 receptor agonists (non-BZD)
Zolpidem, zaleplon, eszopiclone
Characteristics: lipophilic, fast onset of action, short duration of action, little dependence/tolerance/withdraw symptoms, potentiated by ethanol
Zolpidem (Ambien)
o Zolpidem’s -CH3 → inactive metabolites’ -CH2OH inactive metabolite’s –COOH
Zaleplon (Sonata)
o Zaleplon’s -CH3 unstable → (dealkylated) inactive metabolite’s –H minor metabolite’s =O and –H
o Zaleplon’s -CH3 unstable → inactive metabolite’s =O minor metabolite’s =O and –H
Eszopiclone (Lunesta)
o Eszopiclone → (demethylation) –NH
o Eszopiclone → (oxidation) –NO
Barbiturates
Metabolism o Hydroxylation (oxidation) inactive metabolite o N-dealkylation active metabolite o Aromatic hydroxylation o Desulfuration
Pharmacology: respiratory depression, tolerance Propofol & fospropofol
Propofol (Diprivan): short-acting, IV
Fospropfol (Lusedra): water soluble prodrug, less pain at IV catheter site Melatonin
Synthesis in pineal gland under the control of light
Structure: indoleamine o Related to 5-HT o Biosynthesized from tryptophan via 5-HT
Use: jet lag, work shift-change insomnia Ramelteon (Rozerem)
Orally active melatonin receptor agonist high affinity for MT1 & MT2 receptors o Affinity: MT1 > MT2 o MT1: regulates sleepiness o MT2: regulates body shift between day & night
Use: sleep onset difficulty
Ramelteon → =O ester hydrolysis product
Ramelteon → –OH
Advantages: no memory problems (anterograde amnesia) no dependence/withdrawal/rebound, no REM suppression, no restriction on duration of use (can be used for chronic insomnia)
Disadvantages: ↑drug interactions (CYP1A2 metabolism), hepatic concerns, ↑prolactin levels
