SYNTHESIS OF LCYCLOPROPHY]METHYL]-2,6-METHANO-3-BENZAZOCIN-8-OL AND LCYCLOPROPHY]METHYL]-2,6-METHANO-3-BENZAZOCIN-8-OL - COMPARISON OF THE AFFINITIES FOR SIGMA(1) AND OPIOID RECEPTORS WITH IN THE DIASTEREOISOMERIC MPCB AND CCB())

The synthesis and the in vitro receptor affinity for sigma(1) and opio d receptors of the two diastereoisomers of (+)-cis-MPCB namely, (+)-ci s-(1'S,2'R)-6, onyl)-2'-phenylcyclopropyl]methyl]-2,6-(1'S,2'R)6a and cyclopropyl]methyl]-2,6-methano-3-benzazocin-8-ol, (1'R,2'S)6a are rep orted. Affinities of (1'S,2'R)6a and (1'R,2'S)6a were compared with th ose of the (-)-cis-diastereoisomers of MPCB(1), and of its p-Cl phenyl derivative CCB(2). The (+)-cis-N-normetazocine derivatives showed hig her affiniy for the sigma(1) sites, labeled with [H-3]-(+)-pentazocine than the corresponding (-)-cis analogs. In particular, compound (1'S, 2'R)6a showed a Ki = 66.7 nM for or receptor, associated with a good s electivity for sigma(1) with respect to kappa, mu, delta opioid recept ors subtypes (Ki = > 1,000 nM). Analysis of the data seem to support t he hypothesis that the (+)-cis-N-normetazocine nucleus posses a specif ic enantioselectivity for sigma(1) sites, when supporting bulkier N-su bstituents functionalized with a carboxy ester group.