A structure-affinity and comparative molecular field analysis of sigma-2 (sigma2) receptor ligands

Several sigma(1) receptor ligands with sub-nanomolar affinity and excellent selectivity have been reported, but relatively few sigma(2)-selective ligands are known. 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl] piperazine (PB28; 1) has been reported by us as a high-affinity sigma(2) receptor ligand with significant sigma(2) selectivity, and several analogs of (1) now have been developed. Among these are the class of cyclohexylpiperazines that display a good compromise between affinity/activity and selectivity for sigma(2) receptors. Very little is currently known about the nature of sigma(2) receptors. In the absence of structure-based receptor information, we applied a comparative molecular field analysis (CoMFA) - a three-dimensional structure-activity relationship (3D-QSAR) method - to a set of cyclohexylpiperazine sigma(2) ligands to develop a predictive model that might provide information about the stereoelectronic nature of the receptor binding site. Two CoMFA models were generated from two different alignments: the first used an automated FlexS algorithm, and the second used a rationally-driven manual alignment. Significantly better predictivity was obtained with the manual alignment (TSET: q(2) = 0.73, r(2) = 0.95; PSET: r(2) = 0.55/0.73) than from the automated alignment (TSET: q(2) = 0.69, r(2) = 0.98; PSET: r(2) = 0.13/0.16). The resulting CoMFA maps account for observed structure-affinity relationships and suggest a possible anatomy for the sigma(2) receptor/cyclohexylpiperazine binding site.