Sayoko Kanie

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.

Characteristics of TRK-130 (Naltalimide), a Novel Opioid Ligand, as a New Therapeutic Agent for Overactive Bladder

We characterized TRK-130 (N-[(5R,6R,14S)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-yl]phthalimide; naltalimide), an opioid ligand, to clarify the therapeutic potential for overactive bladder (OAB). In radioligand-binding assays with cells expressing human µ-opioid receptors (MORs), δ-opioid receptors (DORs), or κ-opioid receptors (KORs), TRK-130 showed high selectivity for MORs (Ki for MORs, DORs, and KORs = 0.268, 121, and 8.97 nM, respectively). In a functional assay (cAMP accumulation) with cells expressing each human opioid receptor subtype, TRK-130 showed potent but partial agonistic activity for MORs [EC50 (Emax) for MORs, DORs, and KORs = 2.39 nM (66.1%), 26.1 nM (71.0%), and 9.51 nM (62.6%), respectively]. In isovolumetric rhythmic bladder contractions (RBCs) in anesthetized guinea pigs, TRK-130 dose-dependently prolonged the shutdown time (the duration of complete cessation of the bladder contractions) (ED30 = 0.0034 mg/kg i.v.) without affecting amplitude of RBCs. Furthermore, TRK-130 ameliorated formalin-induced frequent urination at doses of higher than 0.01 mg/kg p.o. in guinea pigs under the freely moving condition. Meanwhile, TRK-130 showed only a negligible effect on the gastrointestinal transit at doses of up to 10 mg/kg s.c. in mice. These results indicate that TRK-130 is a potent and selective human MOR partial agonist without undesirable opioid adverse effects such as constipation and enhances the storage function by suppressing the afferent limb of the micturition reflex pathway, suggesting that TRK-130 would be a new therapeutic agent for OAB.