Pharmacological evaluation of the beta-adrenoceptor agonist and thromboxane receptor blocking properties of 1-benzyl substituted trimetoquinol analogues.

The beta 1- and beta 2-adrenoceptor agonist and thromboxane A2 (TXA2) antagonist properties of trimetoquinol (TMQ, I) and 1-benzyl substituted TMQ analogues [3'-iodo-4',5'-dimethoxy TMQ, II; 3',5'-diiodo-4'-dimethoxy TMQ, III; 3',4'-dimethoxy-5'-nitro TMQ, IV; 3',4'-dimethoxy-5'-amino TMQ; V; and 3',4'-dimethoxy TMQ, VI] were studied in guinea pig atria (beta 1) and trachea (beta 2), and in rat thoracic aorta and human platelets, respectively. The rank order of agonist activities in beta 1- and beta 2-adrenoceptor tissues was IV greater than or equal to I greater than II greater than V greater than III greater than VI and I greater than II = IV = V greater than VI greater than III, respectively. An increase of beta 2/beta 1-selectivity (2- to 3-fold) was observed for analogues V and VI as compared to TMQ. The rank order of inhibitory potency against U46619-induced contraction of rat aorta and human platelet aggregation and secretion was the same (I = II = III greater than IV greater than V greater than VI). The results show that varying the substituents at the 3'- and 5'-positions of the trimethoxybenzyl group of TMQ produces compounds which give different profiles of biological activity for beta-adrenoceptor agonism versus TXA2 antagonism. Certain TMQ analogues, notably analogue V, showed a greater selectivity as beta 2-receptor agonists and TXA2 antagonists in vascular smooth muscle than the parent drug (TMQ), and the iodinated analogues (II and III) have promise as potential radioligands or photoaffinity probes for thromboxane A2 receptors.