Pharmacological effect of TRK-380, a novel selective human β3-adrenoceptor agonist, on mammalian detrusor strips.

Objective To clarify the potential of TRK-380 as a drug for overactive bladder in humans by evaluating the agonistic activities for human β-adrenergic receptors (β-ARs) and the relaxing effects on isolated detrusor strips. Methods The agonistic activities for human β-ARs were evaluated in SK-N-MC cells (for human β 3 -ARs) and Chinese hamster ovary cells expressing human β 1 - or human β 2 -ARs using the cyclic adenosine monophosphate accumulation assay. The relaxing effects on the resting tension in isolated detrusor strips from humans, monkeys, dogs, and rats and on carbachol- or KCl-induced contractions in human detrusor strips were evaluated. Results In the cyclic adenosine monophosphate accumulation assay, the agonistic activity of TRK-380 for human β 3 -ARs was potent and equivalent to that of the potent nonselective β-AR agonist isoproterenol and superior to that of selective β 3 -AR agonists, such as BRL-37344 and CL316,243. TRK-380 showed no agonistic activity for human β 1 -ARs and a weak agonistic effect on human β 2 -ARs. In isolated detrusor strips, the concentration-dependent relaxing effects of TRK-380 on the resting tension were equivalent to those of isoproterenol in humans, monkeys, and dogs but weaker than the effects in rats. The selective β 3 -AR antagonist SR59230A shifted the concentration-response curve in a concentration-dependent manner to TRK-380 for the resting tension of human detrusor strips to the right. TRK-380 had a concentration-dependent relaxing effect on the contractile responses to carbachol and KCl in human detrusor strips. Conclusion TRK-380 was a potent and selective human β 3 -AR agonist, and the isolated human detrusor relaxation was mainly mediated by activation of the β 3 -AR. Consequently, TRK-380 might be a promising compound for the treatment of overactive bladder.