THE LIGAND-BINDING SITE OF BUSPIRONE ANALOGS AT THE 5-HT1A RECEPTOR

A three-dimensional model of the 5-HT1A receptor in man was constructe d by molecular-modelling techniques and used to study the molecular in teractions of a series of buspirone analogues with the 5-HT1A receptor by molecular-mechanical-energy minimization and molecular-dynamics si mulations. The receptor has seven trans-membrane a helices (TMHs) orga nized according to the electron-density-projection map of visual rhodo psin, and includes all loops between TMHs and the N- and C-terminal pa rts. The best fit between the buspirone analogues and the receptor mod el was obtained with the quinolinyl part of the ligand molecules inter acting with amino acids in TMH6, the imide group interacting with amin o acids in TMH2, TMH3 and TMH7, and the carbonyl groups hydrogen-bonde d with Ser86 and Ser393. The ligand-binding rank order deduced from th e experimentally determined inhibition constant was reproduced by calc ulation of receptor-binding energies of the buspirone analogues. The m odels suggest that steric hindrance and repulsive forces between the r eceptor and the imide group of the buspirone analogues are the most im portant determinants of ligand-binding affinity for discriminating bet ween these ligands.