Molecular Pharmacology, Vol 6, 189-194, Copyright © 1970 by the American Society for Pharmacology and Experimental Therapeutics

Electronic Molecular Pharmacology: The Benzothiadiazine Antihypertensive Agents

I. Pharmacological Aspects of Tautomerism and Conformation

¹ Department of Pharmacology, & Schering Corporation, Bloomfield, New Jersey 07003

Extended Hückel theory molecular orbital calculations have been carried out on a representative number of antihypertensive benzothiadiazines to determine the role that conformation and tautomeric behavior play in the pharmacology of these compounds, as a preliminary to the multiple regression analyses which form the next paper in this series [A. J. Wohl, Mol. Pharmacol. 6, 195 (1970)]. The results indicate that (a) all compounds studied prefer to exist as the 4-H rather than the 2-H tautomer, in agreement with previous ultraviolet spectroscopy conclusions, and (b) the conformation of substituent groups seems to play a very important role in determining the antihypertensive potency of these substances. The conformation of highly potent cycloalkenyl substituents changes markedly with positional double-bond isomerism, and these changes are reflected directly in the resulting potency.