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Chemistry of Opioids

Opium alkaloids
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


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: > o Met-enkephalin: Tyr-Gly-Gly-Phe-Met o Leu-enkephalin: Tyr-Gly-Gly-Phe-Leu -endorphin: contains Met-enkephalin sequence at amino terminal, opioid receptor Dynorphins: contains Leu-enkephalin sequence at amino terminal Others: endomorphins, neoendorphin, nociceptin

Opioid receptors
G-protein coupled receptors Receptor subtypes o : -endorphin > enkephalins > dynorphins o : enkephalins > endorphins & dynorphins o : dynorphins >> endorphins & enkephalins

Metabolism
Morphine metabolism o Major metabolism pathway: conjugation with glucuronic acid active metabolite (M-6-G) & inactive metabolite (M-3-G) Codeine metabolism o 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


Buprenorphine o Partial agonist activity @ receptor due to metabolite nor-buprenorphine o Partial antagonist activity@ receptor o Antihyperalgesic effect: 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: -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 agonist o Metabolism: O-demethylation by CYP2D6 more potent -receptor agonist (200x affinity) Tapentadol o Indication: moderate to severe pain o MOA: dual action: (+)-receptor & ()NE reuptake o Formulation: IR & PO o SE: tolerability but risk for respiratory depression o Potency: tramadol < tapentadol < morphine