N-Substituent Structure

N-Methyl remains the substituent most commonly associated with agonism, although there are a few examples of N-methyl antagonists and mixed-acting agents (p.428). 

The 30-year old proposal that N-demethylation(dealkylation) of morphine and its congeners is involved in the pharmacological activity of opioids(l42) was based upon the evidence of metabolic studies in the liver and, in consequence, received much criticism. Recent work of Hahn and his col-leagues(143) has revitalized the hypothesis since their data relate to central metabolic processes. Significant facts established by double isotope (6-3H, 1V-14CH3 morphines) techniques are  

The reaction is localized in brain regions which are associated with the presence of opioid receptors and with opioid sites of action. 

The enzyme responsible for brain N-dealkylation is different from the liver enzyme (a cytochrome P-450 mixed function oxidase). 

Dextrorphan and (+)-morphine are not N-demethylated while the corresponding potent levo agonists are biotransformed. 

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