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Chemistry of Opioids Jaki

The document discusses the chemistry of opioids including both natural and synthetic opioids. It describes the structures and properties of important opium alkaloids like morphine and codeine. It also discusses endogenous opioid peptides that are produced in the body and act on opioid receptors. There are three main types of opioid receptors that different opioids can act on as agonists, partial agonists, or antagonists. The document outlines the metabolism and structural features of various opioids as well as prodrugs that are metabolized into more potent opioids.

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324 views3 pages

Chemistry of Opioids Jaki

The document discusses the chemistry of opioids including both natural and synthetic opioids. It describes the structures and properties of important opium alkaloids like morphine and codeine. It also discusses endogenous opioid peptides that are produced in the body and act on opioid receptors. There are three main types of opioid receptors that different opioids can act on as agonists, partial agonists, or antagonists. The document outlines the metabolism and structural features of various opioids as well as prodrugs that are metabolized into more potent opioids.

Uploaded by

drugdrug
Copyright
© Attribution Non-Commercial (BY-NC)
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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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

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