CONFORMATIONAL-ANALYSIS, PHARMACOPHORE IDENTIFICATION, AND COMPARATIVE MOLECULAR-FIELD ANALYSIS OF LIGANDS FOR THE NEUROMODULATORY SIGMA(3)RECEPTOR

Molecular modeling studies were carried out on a series of 1-phenyl-3- amino-1,2,3,4-tetrahydronaphthalenes (phenylaminotetralins, PATs), sev eral PAT structural analogs, and various non-PAT ligands that demonstr ate a range of affinities for a novel sigma(3) receptor linked to stim ulation of tyrosine hydroxylase and dopamine synthesis in rodent brain . In an effort to develop a ligand-binding model for the sigma(3) rece ptor, a pharmacophore mapping program (DISCO) was used to identify str uctural features that are common to ligands that exhibit moderate to h igh binding affinity for sigma(3) sites. DISCO then was utilized to pr opose a common pharmacophoric region that included one low-energy conf ormation of each compound in the training set. The resulting alignment was utilized in a comparative molecular field analysis (CoMFA) study in an attempt to correlate the steric and electrostatic fields of the molecules with the respective binding affinities at the sigma(3) recep tor. A suitably predictive model was obtained from the CoMFA analysis which will be employed in the development of additional PAT analogs th at could potentially display high affinity and selectivity for the sig ma(3) receptor. The excluded volumes which resulted from comparing mol ecular volumes of active and inactive compounds were visualized to exa mine the limits of steric tolerance imposed by the sigma(3) receptor.