Am. Myers et al., CONFORMATIONAL-ANALYSIS, PHARMACOPHORE IDENTIFICATION, AND COMPARATIVE MOLECULAR-FIELD ANALYSIS OF LIGANDS FOR THE NEUROMODULATORY SIGMA(3)RECEPTOR, Journal of medicinal chemistry, 37(24), 1994, pp. 4109-4117
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.