Electronic Molecular Pharmacology: The Benzothiadiazine Antihypertensive Agents: II. Multiple Regression Analyses Relating Biological Potency and Electronic Structure

ARNOLD J. WOHL

Abstract

Extended Hückel Theory calculations have been carried out on a number of antihypertensive benzothiadiazine-1, 1-dioxides in their preferred tautomeric and conformational structures [A. J. Wohl, Mol. Pharmacol. 6, 189 (1970)] in an attempt to define by multiple regression analyses the electronic and steric factors which quantitatively control biological potency. The results indicate that position 5 in the benzenoid portion of the molecule is a center for receptor-drug electron transfer, determined by the energy of the most energetic occupied molecular orbital. Also of importance is the degree of positive charge localized on atom 4 and the substituent group on position 3, as well as the charge on the sulfone oxygen atoms. An intimate sequence of molecular events comprising the mechanism of action is proposed, and a model of receptor structure is offered which accounts for the competitive behavior of these compounds with Ba⁺⁺ and Ca⁺⁺ and is used to predict the potencies of a wide variety of nonselected compounds with high accuracy.

ACKNOWLEDGMENTS The author is deeply indebted to Miss Lorraine M. Hausler and Mrs. Emma Eynon for painstaking collection of pA₂ values, to Dr, J. G. Topliss for synthesis of compounds, to Mrs. Margaret Hanks for needed help in interpretation of the regression analyses, and to Mrs. Barbara Uhrmacher for programming assistance. Neither this nor the preceding paper would have been possible without the help of the Quantum Chemical Program Exchange of Indiana University, which supplied the EHT program (QCPE 64) and the program for calculation of Cartesian atomic coordinates as input to the EHT program as PROXYZ (QCPE 94). Special acknowledgments are due Mr. Robert Meese of the Singer-General Precision Corporate Data Center, for help with the operations and scheduling of SRU 1108 computer time.