Synthesis and in Vitro and in Vivo Activity of (−)-(1<i>R</i>,5<i>R</i>,9<i>R</i>)- and (+)-(1<i>S</i>,5<i>S</i>,9<i>S</i>)-<i>N</i>-Alkenyl-, -<i>N</i>-Alkynyl-, and -<i>N</i>-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 (S,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, σ2/σ1 = 1250, and 1 nM, σ2/σ1 = 750, respectively); in contrast, N-allylnormetazocine (22) had relatively poor affinity at σ1, and its σ1/σ2 ratio was <100

Probes for Narcotic Receptor Mediated Phenomena. 34. Synthesis and Structure−Activity Relationships of a Potent μ-Agonist δ-Antagonist and an Exceedingly Potent Antinociceptive in the Enantiomeric C9-Substituted 5-(3-Hydroxyphenyl)-<i>N</i>-phenylethylmorphan Series

Both of the enantiomers of 5-(3-hydroxyphenyl)-N-phenylethylmorphan with C9α-methyl, C9-methylene, C9-keto, and C9α- and C9β-hydroxy substituents were synthesized and pharmacologically evaluated. Three of the 10 compounds, (1R,5R,9S)-(−)-9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl-2-azabicyclo[3.3.1]nonane ((1R,5R,9S)-(−)-10), (1R,5S)-(+)-5-(3-hydroxyphenyl)-9-methylene-2-phenethyl-2-azabicyclo[3.3.1]nonane ((1R,5S)-(+)-14), and (1R,5S,9R)-(−)-5-(3-hydroxyphenyl)-9-methyl-2-phenethyl-2-azabicyclo[3.3.1]nonane ((1R,5S,9R)-(+)-15) had subnanomolar affinity at μ-opioid receptors (Ki = 0.19, 0.19, and 0.63 nM, respectively). The (1R,5S)-(+)-14 was found to be a μ-opioid agonist and a μ-, δ-, and κ-antagonist in [35S]GTP-γ-S assays and was approximately 50 times more potent than morphine in a number of acute and subchronic pain assays, including thermal and visceral models of nociception. The (1R,5R,9S)-(−)-10 compound with a C9-hydroxy substituent axially oriented to the piperidine ring (C9β-hydroxy) was a μ-agonist about 500 times more potent than morphine. In the single-dose suppression assay, it was greater than 1000 times more potent than morphine. It is the most potent known phenylmorphan antinociceptive. The molecular structures of these compounds were energy minimized with density functional theory at the B3LYP/6-31G* level and then overlaid onto (1R,5R,9S)-(−)-10 using the heavy atoms in the morphan moiety as a common docking point. Based on modeling, the spatial arrangement of the protonated nitrogen atom and the 9β-OH substituent in (1R,5R,9S)-(−)-10 may facilitate the alignment of a putative water chain enabling proton transfer to a nearby proton acceptor group in the μ-opioid receptor