TY - JOUR T1 - Quantum Mechanical Study on the Conformational Properties of Antihistaminic Drugs JF - Molecular Pharmacology JO - Mol Pharmacol SP - 268 LP - 279 VL - 11 IS - 3 AU - B. PULLMAN AU - P. COURRIÈRE AU - H. BERTHOD Y1 - 1975/05/01 UR - http://molpharm.aspetjournals.org/content/11/3/268.abstract N2 - 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—Cβ and Cβ—Cα 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. ER -