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.

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.

Synthesis of new opioid derivatives with a propellane skeleton and their pharmacology: part 1.

The observation that 17-cyclopropylmethylmorphinan derivatives without the 4,5-epoxy ring showed more κ selectivity than those with a 4,5-epoxy ring led us to develop a working hypothesis: the position of the plane composed of the A and B rings would influence the opioid receptor type selectivity and that the decrease in the torsion angle C11-C12-C13-C14 could improve the κ selectivity. Consistent with our hypothesis, KNT-42 with an N-cyclopropylmethyl propellane structure, whose A and B rings were fixed in a torsion angle of approximately 0°, showed κ selective agonist activity.

Design, synthesis, and structure-activity relationship of novel opioid kappa-agonists.

By focusing on 4,5-epoxymorphinan, a traditional opioid skeleton but a new structure in the opioid kappa-agonist research field, and by rationally applying the 'message-address concept' and 'accessory site hypothesis,' we discovered a new chemical class opioid kappa-agonist, TRK-820 (1). Its development as an antipruritus is now in the final stage. Here, the full scope of its design, synthesis, and structure-activity relationship are described.

Synthesis of a stable iminium salt and propellane derivatives.

The treatment of morphinan 1 with NaH and MsCl provided very stable iminium salt 7 possessing propellane skeleton. One of the synthesized iminium salts 7, isobutyl derivative 7b, was crystallized and its structure was determined by X-ray crystallography. The natural bond orbital analysis suggested that the stability of the iminium should result from the stereoelectronic effect (hyperconjugation) attributed to their own structures.

Design and synthesis of a metabolically stable and potent antitussive agent, a novel delta opioid receptor antagonist, TRK-851.

We have previously reported on antitussive effect of (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5',6'-dihydro-3-methoxy-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-14-ol(1b) methanesulfonate (TRK-850), a selective delta opioid receptor antagonist which markedly reduced the number of coughs in a rat cough model. We designed TRK-850 based on naltrindole (NTI), a typical delta opioid receptor antagonist, to improve its permeability through the blood-brain barrier by introducing hydrophobic moieties to NTI. The ED(50) values of NTI and compound 1b by intraperitoneal injections were 104 microg/kg and 2.07 microg/kg, respectively. This increased antitussive potency probably resulted from the improved brain exposure of compound 1b. However, 1b was extremely unstable toward metabolism by cytochrome P450. In this study, we designed and synthesized compound 1b derivatives to improve the metabolic instability, which resulted in affording highly potent and metabolically stable oral antitussive agent (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-8'-fluoro-5',6'-dihydro-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-3,14-diol (1c) methanesulfonate (TRK-851).

Effect of repeated administration of TRK-820, a kappa-opioid receptor agonist, on tolerance to its antinociceptive and sedative actions.

Repeated administration of micro-opioid receptor agonist, morphine induces tolerance not only to the antinociceptive effect but also to other pharmacological effects, resulting in shortened working duration and decreased efficacy. But less is known about kappa-opioid agonist-induced tolerance. The tolerance-development potency of kappa-opioid receptor agonists with a focus on TRK-820 was characterized. After five administrations of kappa-opioid receptor agonists, TRK-820 (0.1-0.8 mg/kg), U-50,488H (10-80 mg/kg) and ICI-199,441 (0.025-0.2 mg/kg) subcutaneously over 3 days, tolerance to the antinociceptive effects, assessed by an acetic acid-induced abdominal constriction test, developed in a repeated dose-dependent manner. The tolerance-development potency of TRK-820 was the least among these kappa-opioid receptor agonists. Similarly, TRK-820 and U-50,488H induced tolerance to their sedative effects as judged by a wheel-running test in mice. Greater tolerance was developed to the sedative effect than to the antinociceptive effect in both compounds. After repeated administration, the number of kappa-opioid receptors in the mouse brain was reduced by U-50,488H (80 mg/kg) but not by TRK-820 (0.4 mg/kg). There was no change of the affinity by the treatment with both compounds. These results demonstrated that the kappa-opioid receptor agonists developed tolerance both to the antinociceptive and the sedative effects, though the tolerance to the sedative effect developed more readily than tolerance to the antinociceptive effect. The difference in the potency for down-regulating the kappa-opioid receptors in the brain may account for the tolerance-development potency of the compounds.