Download Chemistry of Opioids

Chemistry of Opioids
Opium alkaloids
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Alkaloid: naturally occurring compound contain basic nitrogen
Opium: morphine + codeine + thebaine + papaverine + noscapine
Morphine
o Structure: 5 rings, 2 at right angles with each other
o Chirality is key  only the (–) isomer has active analgesic
properties
Codeine = methylated morphine = prodrug
Heroin = diacetylmorphine = morphine + acetic acid
o ↑Lipophilicity  ↑BBB penetration ↑BA
Endogenous opioid peptides
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Endorphin = endogenous + morphine
o Different structure but similar action as morphine
o Tyr as 1st amino acid residue is essential for activity
Enkephalins
o Opioid receptor affinity: δ > μ
o Met-enkephalin: Tyr-Gly-Gly-Phe-Met
o Leu-enkephalin: Tyr-Gly-Gly-Phe-Leu
β-endorphin: contains Met-enkephalin sequence at amino terminal, μ opioid receptor
Dynorphins: contains Leu-enkephalin sequence at amino terminal
Others: endomorphins, neoendorphin, nociceptin
Opioid receptors
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G-protein coupled receptors
Receptor subtypes
o μ: β-endorphin > enkephalins > dynorphins
o δ: enkephalins > endorphins & dynorphins
o κ: dynorphins >> endorphins & enkephalins
Metabolism
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Morphine metabolism
o Major metabolism pathway: conjugation with
glucuronic acid  active metabolite (M-6-G) &
inactive metabolite (M-3-G)
Codeine metabolism
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Codeine (prodrug) →
morphine
o Codeine →
inactive metabolite norcodeine
Prodrugs: have “cod” in them
o Codeine, hydrocodone, oxycodone
 metabolized to more potent opioids
Structure Activity Relationships
Mixed agonist-antagonists
Pure antagonists
Atypical morphine analogues
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Buprenorphine
o Partial agonist activity @ μ receptor due to metabolite nor-buprenorphine
o Partial antagonist activity@ κ receptor
o Antihyperalgesic effect: κ receptor antagonistic activity
o ↓Adverse effects: ↓respiratory depression, not altered by age or renal dysfunction
Meperidine
o Binds to P-site: phenolic ring of meperidine resembles phenylalanine of P-site
o High abuse potential: penetrates BBB quickly, rapid onset
o Metabolism to nor-meperidine via N-demethylation  CNS excitation (e.g. tremors, seizures)
o Inhibits 5-HT reuptake: potential for serotonin syndrome
 Absolute contraindication: meperidine + MAOIs
Fentanyl
o Structural features:
 Extra nitrogen between ring and phenyl group
 ↓CNS toxicities compared to meperidine
 Phenethyl group on piperidine nitrogen
 Binds both T- and P-sites
 80x more potent than morphine, 940x meperidine
o ↑Lipophilicity  quick onset of action, quick metabolism, quick duration of action
Methadone
o Treats heroin withdrawal
o R enantiomer: responsible for main opioid activity
o MOA: μ-receptor agonist, NMDA antagonist, inhibits 5-HT & NE reuptake
o Metabolism: demethylation results in many active metabolites
Tramadol
o Main MOA: inhibits NE & 5-HT reuptake
 NE reuptake inhibition: via (–) enantiomer
 5-HT reuptake inhibition: via (+) enantiomer
o Other MOA: weak μ agonist
o Metabolism: O-demethylation by CYP2D6
 more potent μ-receptor agonist (200x affinity)
Tapentadol
o Indication: moderate to severe pain
o MOA: dual action: (+)μ-receptor & (–)NE reuptake
o Formulation: IR & PO
o SE: ↑tolerability but ↑risk for respiratory depression
o Potency: tramadol < tapentadol < morphine