Synthesis of (+)-(1'R,2'S) and (1'S,2'R)-6,11-Dimethyl-1,2,3,4,5,6- hexahydro-3-[[2'-(alkoxycarbonyl)-2'-phenylcyclopropyl]methyl]-2,6-methano- 3-benzazocin-8-ol. Comparison of the affinities for σ1 and opioid receptors with in the diastereoisomeric MPCB and CCB

The synthesis and the in vitro receptor affinity for σ and opiod receptors of the two diastereoisomers, of (+)-cis-MPCB namely, (+)-cis- (1'S,2'R)-6,11-Dimethyl-1,2,3,4,5,6-hexahydro-3-[[2'-(methoxycarbonyl)-2'- phenylcyclopropyl]methyl]-2,6-methano-3-benzazocin-8-ol, (1'S,2'R)6a and (+)- cis,(1'R,2'S)-6,11-Dimethyl-1,2,3,5,6-hexahydro-3-[[2'-(methoxycabonyl)-2'- phenylcyclopropyl]methyl]-2,6-methano-3-benzazocin-8-ol, (1'R,2'S)6a are reported. Affinities of (1'S,2'R)6a and (1'R,2'S)6a were compared with those of the (-)-cis-diastereoisomers of MPCB(1), and of its p-Cl phenyl derivative CCB(2). The (+)-cis-N-normetazocine derivatives showed higher affinity for the σ1 sites, labeled with [3H]-(+)-pentazocine than the corresponding (- )-cis- analogs. In particular, compound (1'S,2'R)6a showed a Ki = 66.7 nM for σ1 receptor, associated with a good selectivity for σ1 with respect to κ, μ, δ opioid receptors subtypes (Ki = > 1,000 nM). Analysis of the data seem to support the hypothesis that the (+)-cis-N-normetazocine nucleus posses a specific enantioselectivity for σ1 sites, when supporting bulkier N-substituents functionalized with a carboxy ester group.