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.

Mechanisms of inhibitory action of TRK-130 (Naltalimide), a µ-opioid receptor partial agonist, on the micturition reflex.

PURPOSE: To clarify the mechanism of inhibitory action of TRK-130 (Naltalimide), a unique µ-opioid receptor partial agonist, on the micturition reflex. METHODS: The effect of TRK-130 on isovolumetric rhythmic bladder contractions (RBCs) was examined in guinea pigs, the effect of which was clarified by co-treatment with naloxone or in spinal cord transection. The effect of TRK-130 on urodynamic parameters was also observed in guinea pigs. In addition, the effect of TRK-130 on bladder contraction induced by peripheral stimulation of the pelvic nerve was investigated in rats. RESULTS: TRK-130 (0.001-0.01 mg/kg, iv) dose-dependently inhibited RBCs, which was dose-dependently antagonized by naloxone; however, the antagonism susceptibility was different from morphine (1 mg/kg, iv). The minimum effective dose (0.003 mg/kg) of TRK-130 remained similar in spinal cord-transected animals. TRK-130 (0.0025 mg/kg, iv) increased bladder capacity without changing the voiding efficiency, maximum flow rate, and intravesical pressure at the maximum flow rate, whereas oxybutynin (1 mg/kg, iv) increased the bladder capacity but affected the other parameters. TRK-130 (0.005 mg/kg, iv) did not produce significant changes on the bladder contractions induced by peripheral stimulation of the pelvic nerve, while oxybutynin (1 mg/kg, iv) significantly suppressed the bladder contractions. CONCLUSIONS: These results suggest that TRK-130 enhances the bladder storage function by modulating the afferent limb of the micturition reflex through µ-opioid receptors in the spinal cord. TRK-130 could be a more effective and safer therapeutic agent with a different fashion from antimuscarinics and conventional opioids for overactive bladder.

TRK-380, a novel selective human ß3-adrenoceptor agonist, ameliorates formalin-induced pollakiuria in rats and carbachol-induced bladder contraction in dogs.

OBJECTIVE: To investigate the effects of TRK-380, a selective ß3-adrenoceptor (ß3-AR) agonist, on voiding behavior in rats with pollakiuria and on carbachol (CCh)-induced bladder contraction in dogs. METHODS: The voiding behavior of female Sprague Dawley rats was recorded continuously with a balance. Rats were intravesically pretreated with 2.5% formalin under isoflurane anesthesia. The next day, the effect of TRK-380 (7.5-30 mg/kg, orally) or tolterodine, an antimuscarinic drug (3.75-15 mg/kg, orally), on the voiding frequency was evaluated. In another experiment, male beagle dogs were anesthetized with pentobarbital, CCh (3 µg/kg, intravenously) was administered to them, and the effect of TRK-380 (0.1 or 0.3 µg/kg/minute, intravenously infusion) on CCh-induced bladder contraction was evaluated. RESULTS: Rats treated with formalin showed a significant increase in the voiding frequency compared with the sham group, and the increase in it was significantly and dose-dependently suppressed by TRK-380 at doses of ≥15 mg/kg. In contrast, tolterodine did not lead to a significant change in the voiding frequency even at the highest dose. In dogs, CCh-induced bladder contraction was dose-dependently suppressed by TRK-380; the plasma concentration required for 30% suppression of the CCh-induced bladder contraction (30% relaxation) was 4.90 ng/mL. CONCLUSION: This study indicated that TRK-380 ameliorated pollakiuria, which was resistant to an antimuscarinic drug, and that it also suppressed the bladder contraction induced by cholinergic stimulation in dogs, whose bladder relaxation is known to be predominantly mediated by ß3-ARs, as in humans. These data strengthen the therapeutic potential of ß3-AR for the treatment of overactive bladder.

Pharmacological effect of TRK-380, a novel selective human ß3-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 ß-adrenergic receptors (ß-ARs) and the relaxing effects on isolated detrusor strips. METHODS: The agonistic activities for human ß-ARs were evaluated in SK-N-MC cells (for human ß(3)-ARs) and Chinese hamster ovary cells expressing human ß(1)- or human ß(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 ß(3)-ARs was potent and equivalent to that of the potent nonselective ß-AR agonist isoproterenol and superior to that of selective ß(3)-AR agonists, such as BRL-37344 and CL316,243. TRK-380 showed no agonistic activity for human ß(1)-ARs and a weak agonistic effect on human ß(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 ß(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 ß(3)-AR agonist, and the isolated human detrusor relaxation was mainly mediated by activation of the ß(3)-AR. Consequently, TRK-380 might be a promising compound for the treatment of overactive bladder.