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

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 (