STRUCTURE‐ACTIVITY RELATIONSHIPS OF CLONIDINE‐ AND TOLAZOLINE‐LIKE COMPOUNDS AT HISTAMINE AND α‐ADRENOCEPTOR SITES

Abstract

1 Thirty clonidine- and tolazoline-like compounds with differing phenyl ring substituents were tested for agonistic actions at histamine H₁-receptors (guinea-pig ileum), histamine H₂-receptors (guinea-pig driven right ventricular strips), post-junctional α-adrenoceptors (rat desheathed vas deferens) and pre-junctional α-adrenoceptors (inhibition of sympathetic stimulation in guinea-pig driven left atria). 2 All compounds were inactive at histamine H₁-receptors, while 21 of the 30 compounds displayed varying stimulant activity at H₂-receptors. 3 At post-junctional α-receptors all 30 compounds produced stimulant actions, whereas at prejunctional α-receptors the compounds displayed either agonistic or antagonistic actions. 4 Thus structure-activity relationships (SAR) could only be validated for histamine H₂- and post-junctional α-receptor effects. These studies show that the most potent compounds are those with 2,6-phenyl substituents in which rotation is restricted so that the two rings are aplanar. Electronic effects of the substituents have a greater influence on activity at H₂- than at α-receptors. 5 The major difference in SAR involves the influence of substituents in the 3, 4 or 5 positions on the phenyl ring. The presence of these substituents abolish significant activity at H₂-receptors, while α-receptor stimulant activity is retained.