Synthesis and in vitro and in vivo activity of (-)-(1R,5R,9R)- and (+)-(1S,5S,9S)-N-alkenyl-, -N-alkynyl-, and -N-cyanoalkyl-5,9-dimethyl-2′-hydroxy-6,7-benzomorphan homologues

E. L. May, A. E. Jacobson, M. V. Mattson, J. R. Traynor, J. H. Woods, L. S. Harris, E. R. Bowman, M. D. Aceto

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Two of the synthesized (-)-(1R,5R,9R)-N-homologues (N-but-3-enyl- and N-but-3-ynyl-5,9-dimethyl-2′-hydroxy-6,7-benzomorphan (9, 13)) were found to be about 20 times more potent than morphine in the mouse tail-flick assay (ED50 = 0.05 mg/kg), and (-)-(1R,5R,9R)-N-but-2-ynyl-5,9-dimethyl-2′-hydroxy-6,7-benzomorphan ((-)-(1R,5R,9R)-N-but-2-ynylnormetazocine, 12) was about as potent as the opioid antagonist N-allylnormetazocine (AD50 in the tail-flick vs morphine assay = 0.3 mg/kg). All of the homologues examined had higher affinity for the κ-opioid receptor than the μ-receptor except (-)-N-but-2-ynyl-normetazocine (12), which had a κ/μ ratio = 7.8 and a δ/μ ratio = 118. The (-)-N-2-cyanoethyl (3), -allyl (8), and -but-3-ynyl (13) analogues had good affinity (<10 nM) for δ-opioid receptors. Two homologues in the (+)-(1S,5S,9S)-normetazocine series, N-pent-4-enyl (24) and N-hex-5-enyl (25), were high-affinity and selective σ1-ligands (Ki = 2 nM, σ21 = 1250, and 1 nM, σ2/σ1 = 750, respectively); in contrast, N-allylnormetazocine (22) had relatively poor affinity at σ1, and its σ12 ratio was < 100.

Original languageEnglish (US)
Pages (from-to)5030-5036
Number of pages7
JournalJournal of Medicinal Chemistry
Volume43
Issue number26
DOIs
StatePublished - Dec 28 2000
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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