Potential energy functions and the role of the conformational entropy of clonidine-like imidazolidines in determining their affinity for alpha-adrenergic receptors

F Avbelj and D Hadzi

Energy as a function of the ring interplanar torsional angle was calculated for 12 2-(phenylimino)imidazolidines by the method of perturbation configuration interaction using localized orbitals. The potential energy functions indicate that the molecules may assume any conformation within rather broad limits. The functions were used in calculating the gas phase and solution conformational entropies. The latter were used as the independent variable in regression analysis to derive equations connecting the conformational entropy with pKi (pKi = - log Ki) for [3H]clonidine displacement (literature data). As a comparison, correlations between pKi and several other parameters (modified neglect of diatomic overlap-computed highest occupied and lowest unoccupied molecular orbital energies and dipole moments; pKa; log P; substituent steric parameters) were sought. Correlation coefficients C greater than 0.6 were obtained with the conformational entropy (-0.77), and the ortho steric parameters (-0.71). The correlation with the conformational entropy was not markedly improved by adding other parameters in multiple regression analysis. This result is discussed in terms of the contribution to the ligand-receptor complexation free energy arising from the conformational restriction of the ligands upon binding to the receptor.

Volume 27, Issue 4, pp. 466-470, 04/01/1985
Copyright © 1985 by American Society for Pharmacology and Experimental Therapeutics