The binding of the optical isomers of methadone, alpha-methadol, alpha-acetylmethadol and their N-demethylated derivatives to the opiate receptors of rat brain.
The optical isomers of methadone, alpha-methadol, alpha-acetylmethadol and their N-demethylated derivatives have been systematically studied for their effects on the binding of 3H-dihydromorphine (3H-DHM) and 3H-naloxone (3H-NLX) to opiate receptors in rat brain homogenate. The relative affinities of these agents in competing for both 3H-DHM and 3H-NLX binding parallel their analgesic effects. 1-Methadone is about 30 times as effective as d-methadone in competing for both 3H-DHM and 3H-NLX binding sites. The reduction of 1-methadone to alpha-d-methadol and subsequent N-demethylation to alpha-d-normethadol reduce its effectiveness as indicated by the increase in the IC50 values for both 3H-DHM and 3H-NLX binding. The reduction of d-methadone followed by N-demethylation produces a potent derivative, alpha-1-normethadol, which has IC50 values on 3H-DHM and 3H-NLX binding similar to those of 1-methadone. The affinity of alpha-1-acetyl-methadol on the binding of both 3H-ligands falls between those of 1-methadone and d-methadone, and increases as it is N-demethylated. alpha-d-Acetyl-methadol is more effective than alpha-1-acetylmethadol in competing for both 3H-ligands from the opiate receptors, and its affinity, unlike that of alpha-1-acetylmethadol, decreases when it is N-demethylated. The affinities of the methadone isomers and related compounds on the binding of 3H-NLX fall in the presence of Na+. The latter property indicates the agonistic nature of this series of druges.
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003640:Dealkylation; D004091:Hydromorphone / Q000378:metabolism; D066298:In Vitro Techniques; D007536:Isomerism; D008691:Methadone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008692:Methadyl Acetate / Q000494:pharmacology*; D009270:Naloxone / Q000378:metabolism; D051381:Rats; D011955:Receptors, Drug / Q000187:drug effects
D011955:Receptors, Drug; D009270:Naloxone; D008692:Methadyl Acetate; D004091:Hydromorphone; D008691:Methadone