title: A structure-affinity and comparative molecular field analysis of sigma-2 (sigma2) receptor ligands.
abstract: 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.
authors.affiliation: Dipartimento Farmacochimico, Università degli Studi di Bari, via E. Orabona 4, 70125 Bari, Italy. abate@farmchim.uniba.it
authors.forename: Carmen
authors.initials: C
authors.lastname: Abate
authors.forename: Philip Daniel
authors.initials: PD
authors.lastname: Mosier
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
mesh_terms: D000818:Animals; D008401:Gas Chromatography-Mass Spectrometry; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008024:Ligands; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000819:agonists / Q000737:chemistry / Q000187:drug effects*; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
chemical_list: D007202:Indicators and Reagents; D008024:Ligands; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C106107:sigma-2 receptor