Synthesis and structure-affinity relationships of 1,3,5-alkylsubstituted cyclohexylamines binding at NMDA receptor PCP site

A series of 1,3,5-alkylsubstituted cyclohexylamines 2 were synthesized as l igands for the N-methyl-D-aspartate (NMDA) receptor phencyclidine (PCP) bin ding site. Pure diastereomers with defined configuration of amino group 2-a x and 2-eq were obtained. The optimal size of 1,3,5-substituents was determ ined for cyclohexylamines 2 with an equatorial amino group in the lowest en ergy conformation using Hansch analysis. According to the data, the lipophi lic part of cyclohexylamines 2 does not discriminate between hydrophobic re gions of the PCP binding site but rather recognizes this site as a whole li pophilic pocket. (C) 2000 Editions scientifiques et medicales Elsevier SAS.