Molecular Pharmacology, Vol 11, 268-279, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

Quantum Mechanical Study on the Conformational Properties of Antihistaminic Drugs

¹ Institut de Biologie Physico-Chimique, Laboratoire de Biochimie Théorique associé au Centre National de La Recherche Scientifique, Paris France 75005

The method of perturbative configuration interaction using localized orbitals (PCILO) was applied to the study of the conformational properties of flexible antihistamines of the general formula

See PDF for Equation

with X = N (ethylenediamine derivatives), CH—O (diphenhydramine), and saturated C (pheniramine). Conformational energy maps were constructed as a function of rotation about the X—C and C—C bonds for isolated protonated molecules (for two possible orientations of the cationic head) and for the hydrated derivatives carrying a hydrogenbonded water molecule attached to N⁺H. The computations predict a strong predominance of the gauche form for all the isolated molecules, owing to electrostatic interaction between the cationic head and the esteric oxygen in diphenhydramine, but resulting from hydrogen bonding between the cationic head and the pyridyl nitrogen in pheniramine and the ethylenediamine derivative. In water they predict the coexistence of gauche and trans conformers. Evaluation of the relative populations of these conformers indicates that the proportion of the trans conformer should vary inversely with the electronegativity of the X atom of the chain. The effect of flexibility was studied, using pheniramine as an example. The theoretical results were compared with the available experimental data from X-ray crystal structures and NMR and circular dichroism studies in solution.