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 ((-)-(LR,5R,SR)-N-but-2-ynylnormetazocine, 12) was about as potent as the opioid antagonist N-allylnormetazocine (AD(50) in the tail-flick vs morphine assay 0.3 mg/kg). All of the homologues examined had higher affinity for the kappa -opioid receptor than the mu -receptor except (-)-N-but-2-ynyl-normetazocine (12), which had a kappa/mu ratio = 7.8 and a delta/mu ratio = 118. The (-)-N-2-cyanoethyl . (3), -allyl (8), and -but-3-ynyl (13) analogues had good affinity (<10 nM) for -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 sigma (1)-ligands (K-i = 2 nM, sigma (2)/sigma (1) = 1250, and 1 nM, sigma (2)/sigma (1) 750, respectively); in contrast, N-allylnormetazocine (22) had relatively poor affinity at or, and its sigma (1)/sigma (2) ratio was <100.