VESAMICOL ANALOGS AS SIGMA-LIGANDS - MOLECULAR DETERMINANTS OF SELECTIVITY AT THE VESAMICOL RECEPTOR

The present study compares the affinities of 2-(4-phenylpiperidino)cyc lohexanol (vesamicol, 1) and selected analogues of the latter at the v esamicol receptor (VR) with the corresponding affinities at sigma 1 an d sigma 2 binding sites. For this study, the parent structure 1 was di vided into three fragments: A (cyclohexyl), B (piperidyl) and C (pheny l). Vesamicol analogues were then selected to reflect structural modif ications in these fragments. Consistent with earlier reports, vesamico l was found to exhibit nanomolar affinities at the VR and sigma 1 and sigma 2 sites, resulting in poor selectivity for the VR over the sigma sites. Vesamicol analogues characterized by an acyclic A-fragment sho wed moderate to low affinities at the VR and moderate to high affiniti es at sigma 1 and sigma 2 sites. As a result, many of these analogues showed poor selectivity for the VR. Replacement of the C4 carbon of 1 with a halobenzyl amine resulted in higher affinities at the VR couple d with moderate to low affinities at sigma 1 and sigma 2 sites. The in troduction of a benzofused substituent at the C4 and C5 positions of 1 (compound 2) resulted in a 200-fold increase in affinity at the VR ac companied by a 5- to 6-fold decrease in affinity at sigma 1 and sigma 2 sites relative to the parent structure. Consequently, compound 2 sho wed 12,000-fold higher affinity at the VR than at sigma sites. Restric ting the rotation of fragment C relative to B (by means of alkyl and a lkenyl bridges) generally yielded analogues with subnanomolar affiniti es at the VR. The corresponding affinities of these spirofused conform ationally restricted analogues were moderate to poor at sigma 1 and si gma 2 sites when fragment A was preserved. In contrast, the affinities at sigma 1 and sigma 2 sites were decreased 3- to 11-fold when fragme nt A was modified at position C4 and decreased up to 100-fold with ben zofusion at the C4 and C5 positions of fragment A. Consequently, the s pirofused analogues 15-19 were among the most selective VR ligands exa mined. Thus, the effect of conformational restriction in fragments A a nd B-C is to increase affinity at the VR while decreasing affinity at sigma 1 and sigma 2 sites, and thereby increasing selectivity for the VR over the sigma sites.