QSAR in DBH-Blocking and Hypotensive Fusaric Acid Derivatives

Abstract

Twenty-two fusaric acid derivs. (I; R2 = H, OMe, OEt, Cl, or NO2; R1 = H, halo, alkyl, O-alkyl, CO2H, etc.) and picolinic acid [98-98-6] were tested for dopamine b-hydroxylase (DBH) [9013-38-1] inhibition in vitro as well as for their effects on blood pressure in rats; QSAR of this data was carried out using the Hansch approach. QSARs of DBH inhibition differed with the enzyme prepn. (Cu2+ excess or without Cu2+ excess). With Cu2+ excess, pI50 values were dependent on acidity, basicity, as well as Cu2+ complex formation consts. (an increased ability to form complexes favored DBH inhibition). Inhibition of DBH without Cu2+ excess was dependent on electronic and steric influences of substituents in the 5-position of the pyridine nucleus; electron-donating and bulky groups were favorable. These differences of the QSARs suggest that the mechanism by which fusaric acid [536-69-6], and picolinic acid act at DBH is altered according to the presence or absence of a Cu2+ excess. Use of multivariate statistical methods (e.g. discriminant and variance anal.) to gain insight into the dependence of antihypertensive activity on DBH inhibition and hydrophobicity indicated that for antihypertensive activity of fusaric and picolinic acids, sufficiently high DBH inhibition as well as hydrophobic substituents, esp. in the 5-position of the pyridine nucleus, are necessary.