Faculty Collaboration Database

A structure-affinity and comparative molecular field analysis of sigma-2 (sigma2) receptor ligands. Cent Nerv Syst Agents Med Chem 2009 Sep;9(3):246-57

Date

12/22/2009

Pubmed ID

20021358

DOI

10.2174/1871524910909030246

Scopus ID

2-s2.0-69249154176 (requires institutional sign-in at Scopus site)   33 Citations

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.

Author List

Abate C, Mosier PD, Berardi F, Glennon RA

Author

Philip Mosier PhD Assistant Professor in the School of Pharmacy Administration department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Gas Chromatography-Mass Spectrometry
In Vitro Techniques
Indicators and Reagents
Ligands
Liver
Magnetic Resonance Spectroscopy
Male
Models, Molecular
Molecular Conformation
Quantitative Structure-Activity Relationship
Rats
Rats, Wistar
Receptors, sigma
Structure-Activity Relationship