Substituted 1-phenyl-2-cyclopropylmethylamines with high affinity and selectivity for sigma sites

A series of 1-phenyl-2-cyclopropylmethylamines structurally related to (+)- and (-)-MPCB were synthesized and their binding affinities for or, oz, opi oid and dopamine (D-2) receptors were evaluated. Substitution of the cis-N- normetazocine with different aminic moieties provided compounds with high a ffinity and selectivity for sigma binding sites with respect to opioid and dopamine (D2) receptors. The observed increase in sigma(2) affinity as comp ared to the parent(+)-MPCB, supports the idea that the particular stereoche mistry of (+)-cis-N-normetazocine affects sigma(1) selectivity but does not affect ol affinity. The (+/-)-cis isomers of methyl 2-[(1-adamantylamino)m ethyl]-1-phenylcyclopropane-1-carboxylate (18) displayed a higher affinity and selectivity for the ol and sigma(2) receptor subtypes compared to the ( +/-)-trans 19. interestingly, the enantiomer (-)-cis 18 displayed a prefere nce for ol receptor subtype whereas the (+)-cis 18 did for sigma(2). These results prompt us to synthesize compounds with modification of nitrogen and carboxyl groups. The compounds obtained showed high affinities and selecti vity for sigma sites. Moreover, modifications of carboxyl groups provided c ompounds with the highest affinities in the series. In particular, compound 25 with reverse-type ester showed a K-i of 0.6 and 4.05 nM for sigma(1) an d sigma(2) binding sites, respectively. (C) 2000 Elsevier Science Ltd. All rights reserved.