2,5-Dimethyl-2'-hydroxy-9 alpha- and 9 beta-(3-methylbutyl)-6,7-benzomorphans and N-substituted compounds in the 9 alpha-(3-methylbutyl) series: chemistry, pharmacology, and biochemistry.
2,5-Dimethyl-2'-hydroxy-9 alpha-(3-methylbutyl)-6,7-benzomorphan, the 9 beta-analogue, and 9 alpha-N-substituted (N-ethyl, propyl, butyl, pentyl, hexyl, phenylethyl, allyl, and cyclopropylmethyl) compounds were synthesized and evaluated biochemically and pharmacologically. The 9 beta N-methyl compound was found to be as potent as morphine in the mouse hot plate assay and had one-seventh the affinity of morphine for the opioid receptor. The N-alkyl and N-phenethyl 9 alpha-substituted compounds were either inactive or relatively ineffective as antinociceptive agents. None of the examined compounds substituted for morphine in single-dose suppression studies in the rhesus monkey. The N-cyclopropylmethyl compound in the 9 alpha series had half the narcotic antagonist potency of nalorphine and one-eighth of its affinity for the opioid receptor. The 9 alpha-(3-methylbutyl) moiety, unlike bulky substituents in the 9 beta position of 6,7-benzomorphans, generally lowers affinity for the mu opioid receptor and diminishes their in vivo activity as agonists or antagonists.
D000700:Analgesics / Q000138:chemical synthesis* / Q000378:metabolism; D000818:Animals; D001575:Benzomorphans / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009019:Morphinans / Q000138:chemical synthesis*; D009021:Morphine Dependence / Q000503:physiopathology; D009292:Narcotic Antagonists / Q000138:chemical synthesis; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism; D017450:Receptors, Opioid, mu
D000700:Analgesics; D001575:Benzomorphans; D009019:Morphinans; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu