2,5-Dimethyl-2′-hydroxy-9α- and 9β-(3-Methylbutyl)-6,7-benzomorphans and N-Substituted Compounds in the 9α-(3-Methylbutyl) Series: Chemistry, Pharmacology, and Biochemistry

• Published in: Journal of pharmaceutical sciences 1987-03, Vol.76 (3), p.248-252
• Main Authors: Jacobson, Arthur E., Rice, Kenner C., Burke, Terrence R., Lupinacci, Lillian, Mattson, Mariena V., Aceto, Mario D., Harris, Louis S.
• Format: Article
• Language: English
• Subjects: Analgesics - chemical synthesis; Analgesics - metabolism; Animals; Benzomorphans - chemical synthesis; Benzomorphans - metabolism; Benzomorphans - pharmacology; Brain - metabolism; Chemistry; Exact sciences and technology; Female; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; In Vitro Techniques; Macaca mulatta; Male; Mice; Morphinans - chemical synthesis; Morphine Dependence - physiopathology; Narcotic Antagonists - chemical synthesis; Organic chemistry; Preparations and properties; Rats; Rats, Inbred Strains; Receptors, Opioid - metabolism; Receptors, Opioid, mu
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.2600760315

2,5-Dimethyl-2′-hydroxy-9α-(3-methylbutyl)-6,7-benzomorphan, the 9β-analogue, and 9α-N-substituted (N-ethyl, propyl, butyl, pentyl, hexyl, phenylethyl, allyl, and cyclopropylmethyl) compounds were synthesized and evaluated biochemically and pharmacologically. The 9β 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 9α-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 9α series had half the narcotic antagonist potency of nalorphine and one-eighth of its affinity for the opioid receptor. The 9α-(3-methylbutyl) moiety, unlike bulky substituents in the 9β position of 6,7-benzomorphans, generally lowers affinity for the μ opioid receptor and diminishes their in vivo activity as agonists or antagonists.