Muscarinic M positive allosteric modulator ASP8302 enhances bladder contraction and improves voiding dysfunction in rats.

Objectives: Muscarinic M (M ) receptors mediate cholinergic smooth muscle contraction of the bladder. Current drugs targeting bladder M receptors for micturition disorders have a risk of cholinergic side effects due to excessive receptor activation and insufficient selectivity. We investigated the effect of ASP8302, a novel positive allosteric modulator (PAM) of M receptors, on bladder function in rats.

Modulation of urinary frequency via type 1 lysophosphatidic acid receptors: Effect of the novel antagonist ASP6432 in conscious rats.

Bladder dysfunctions associated with benign prostatic hyperplasia are not sufficiently alleviated by current pharmacotherapies. Lysophosphatidic acid (LPA) is a phospholipid with diverse biological effects. LPA modulates prostate and urethral contraction via the type 1 LPA (LPA) receptor, suggesting the potential of the LPA receptor as a therapeutic target.

Effect of Selective Prostaglandin E2 EP2 Receptor Agonist CP-533,536 on Voiding Efficiency in Rats with Midodrine-Induced Functional Urethral Obstruction.

Objectives: We investigated the effect of the selective prostaglandin E2 EP2 receptor agonist CP-533,536 on voiding efficiency in rats with midodrine-induced functional urethral obstruction.

Methods: The effect of CP-533,536 (0.03-0.

Antiemetic effect of a potent and selective neurokinin-1 receptor antagonist, FK886, on cisplatin-induced acute and delayed emesis in ferrets.

The antiemetic effect of a potent and selective neurokinin-1 (NK1) receptor antagonist, FK886 ([3,5-bis(trifluoromethyl)phenyl][(2R)-2-(3-hydroxy-4-methylbenzyl)-4-{2-[(2S)-2-(methoxymethyl)morpholin-4-yl]ethyl}piperazin-1-yl]methanone dihydrochloride), on cisplatin-induced acute and delayed emesis in ferrets was studied. Intravenous administration of FK886 dose-dependently inhibited cisplatin (10 mg/kg)-induced acute emesis with a minimum effective dose (MED) of 0.32 mg/kg.

Antiemetic effects of a potent and selective neurokinin-1 receptor antagonist, FK886, on cisplatin- and apomorphine-induced emesis in dogs.

The antiemetic properties of a novel neurokinin-1 (NK1) receptor antagonist, FK886 ([3,5-bis(trifluoromethyl)phenyl][(2R)-2-(3-hydroxy-4-methylbenzyl)-4-{2-[(2S)-2-(methoxymethyl)morpholin-4-yl]ethyl}piperazin-1-yl]methanone dihydrochloride), were studied in dog models of cisplatin- and apomorphine-induced emesis. Intravenously administered FK886 (0.32-1 mg/kg) significantly inhibited cisplatin-induced acute emesis during the 5-h observation period.

Pharmacological properties of FK886, a new, centrally active neurokinin-1 receptor antagonist.

The pharmacological properties of the novel neurokinin-1 (NK(1)) receptor antagonist FK886, ([3,5-bis(trifluoromethyl)phenyl][(2R)-2-(3-hydroxy-4-methylbenzyl)-4-{2-[(2S)-2-(methoxymethyl)morpholin-4-yl]ethyl}piperazin-1-yl]methanone dihydrochloride), were studied. FK886 potently inhibited the binding of [(125)I]Bolton-Hunter-labeled substance P ([(125)I]BH-SP; 100 pM) to human NK(1) receptors expressed in Chinese hamster ovary (CHO) cells (IC(50)=0.70 nM).

Inhibitory effect of zacopride on Cisplatin-induced delayed emesis in ferrets.

We evaluated the antiemetic effect of zacopride, a potent 5-HT3-receptor antagonist with 5-HT4-receptor agonist properties, on delayed emesis caused by cisplatin (5 mg/kg, i.p.) in ferrets, compared with granisetron, a selective 5-HT3-receptor antagonist.

Antiemetic activity of FK1052, a 5-HT3- and 5-HT4-receptor antagonist, in Suncus murinus and ferrets.

We investigated the effect of FK1052 [(+)-8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one hydrochloride], a 5-HT3- and 5-HT4-receptor antagonist, on the emesis induced by motion stimuli, copper sulfate, or cisplatin in either Suncus murinus or ferrets and also clarified the role of the 5-HT3 and 5-HT4 receptors in these models. In Suncus murinus, oral administration of FK1052 (100 microg/kg) completely prevented emesis induced by cisplatin (18 mg/kg, i.p.

Diphenidol has no actual broad antiemetic activity in dogs and ferrets.

Previous studies showed that diphenidol was effective on emetogens-induced pica, eating of non-nutritive substances, in rats, a model analogous to emesis in other species. We evaluated the actual antiemetic activity of diphenidol against four emetic stimuli in the dog and ferret, animals that possess an emetic reflex. In dogs, emetic responses to apomorphine were significantly prevented by diphenidol (3.

Contribution of tachykinin receptor subtypes to micturition reflex in guinea pigs.

The aim of the present study was to determine the role of tachykinin in the micturition reflex in guinea pigs. We investigated the effects of tachykinin NK(1) receptor antagonists, GR205171 ([2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-(2S-phenyl-piperidin-3S-yl)-amine), CP99994 ((+), (2R, 3R)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine) and FK888 (N(2)-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl) carbonyl-L-prolyl]-N-methyl-N-phenylmethyl-3-(2-naphthyl)-L-alaninamide), the tachykinin NK(2) receptor antagonist, SR48968 ((+)-N-methyl-[4-(4-acetylamino-4-phenyl piperidino)-2-(3, 4-dichloro-phenyl)butyl] benzamide), and the tachykinin NK(3) receptor antagonist, SB223412 ((S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide) on rhythmic bladder contraction. GR205171 and CP99994 but not SR48968 or SB223412 reduced bladder contraction frequency.

Resiniferatoxin antagonizes cisplatin-induced emesis in dogs and ferrets.

We evaluated the antiemetic activity of resiniferatoxin, an ultrapotent capsaicin analogue, on cisplatin- and apomorphine-induced emesis in dogs, and on cisplatin-induced acute and delayed emesis in ferrets. In the dog, resiniferatoxin (10 microg/kg, s.c.