PHARMACOLOGICAL ACTIVITIES OF TRIMETOQUINOL AND 1-BENZYL HALOGEN-SUBSTITUTED ANALOGS ON RAT BETA-ADRENOCEPTOR SUBTYPES

The beta-adrenoceptor activity profile of trimetoquinol and its 1-benz yl halogen-substituted analogues was studied in rat tissues containing primarily beta(1) (atria)-, beta(2) (trachea)- and atypical beta/beta (3) (distal colon and brown adipose tissue)-adrenoceptors. Functional biological activity resided in the (-)-isomer of trimetoquinol which w as 112-, 275-, 372- and 513-fold more potent than (+)-trimetoquinol in trachea, right atria, distal colon and brown adipose tissue, respecti vely. (+/-)-Trimetoquinol was equally or slightly less active than (-) -trimetoquinol. The 1-benzyl halogen-substituted analogues of trimetoq uinol exhibited differential activation of beta-adrenoceptor subtypes. In functional assays, 3'-iodotrimetoquinol was a potent activator of all beta-adrenoceptor subtypes. 3',5'-Diiodotrimetoquinol was 10-fold more potent as an agonist in tissues containing atypical beta/beta(3)- adrenoceptors than those tissues containing beta(1)- and beta(2)-adren oceptor sites, Furthermore, this drug was a partial agonist as compare d to (+/-)-trimetoquinol and 3'-iodotrimetoquinol on beta(1)-adrenocep tors. Pharmacological properties of the compounds on rat beta(3)-adren oceptors expressed in Chinese hamster ovary (CHO) cells were consisten t with results observed in functional assays. 3',5'-Diiodotrimetoquino l possessed the greatest potency for activation of adenylyl cyclase. R ank order of affinity for rat beta(3)-adrenoceptor was 3'-iodotrimetoq uinol = 3/,5'-diiodotrimetoquinol > (+/-)-trimetoquinol > (-)isoprenal ine. These results suggest that 3',5'-diiodotrimetoquinol is a promisi ng drug for further chemical modification in the development of select ive beta(3)-adrenoceptor ligands.