1.Effects of RPR 100893, a potent NK1 antagonist, on the jaw-opening reflex in the guinea pig.
Alia S1, Azérad J, Pollin B. Brain Res. 1998 Mar 16;787(1):99-106.
RPR 100893 appears as a new potent NK1 selective non-peptide antagonist both in vitro and in vivo, and exhibits high affinity for guinea pig and human NK1 receptor [M. Tabart, J.-F. Peyronel, Synthesis of RPR 100893, prototype of a new series of potent and selective non-peptide NK1 antagonists: the triarylperhydroisoindolols, Bioorg. Med. Chem. Lett., 4 (1994) 673-676.]. Intra-oral administration of RPR 100893 (3, 15, 10, 30 mg/kg) was performed in freely moving guinea pigs during recording of the short- (6-10 ms) and long-latency (18-26 ms) jaw-opening reflex (JOR) elicited by electrical stimulation (0.5 Hz) of the lower incisor tooth pulp. RPR 100893 induced a noticeable and dose-dependent increase of the long-latency reflex thresholds (P<0. 001) but was ineffective on the short-latency responses (P=0.14). The results suggest that, in guinea pigs, the long-latency JOR requires activation of NK1 receptors, while the earlier reflex component, elicited by activation of periodontal afferents, does not.
2.Stimulatory effect of a specific substance P antagonist (RPR 100893) of the human NK1 receptor on the estradiol-induced LH and FSH surges in the ovariectomized cynomolgus monkey.
Kerdelhué B1, Gordon K, Williams R, Lenoir V, Fardin V, Chevalier P, Garret C, Duval P, Kolm P, Hodgen G, Jones H, Jones GS. J Neurosci Res. 1997 Oct 1;50(1):94-103.
Utilizing a human NK1 receptor antagonist (RPR 100893), the present in vivo study was designed to test the hypothesis that endogenous substance P (SP) modulates the action of 17beta-estradiol in inducing luteinizing hormone (LH) and follicle stimulating hormone (FSH) surges in ovariectomized cynomolgus monkey. Plasma concentrations of LH and FSH as well as NK1 receptor antagonist and SP were measured during the development of the negative and positive feedback phases which follow a single administration of estradiol benzoate (50 microg/kg) to long-term ovariectomized monkeys. Daily administration by gastric intubation of 1 mg/kg or 10 mg/kg of the NK1 receptor antagonist (RPR 100893) leads to detectable levels of the antagonist in the blood of treated animals for at least 6 hr after its administration. These levels are in agreement with the experimentally determined IC50 value of the antagonist. The most striking finding of this study is that LH and FSH releases are enhanced during the descending arm of the estradiol benzoate-induced LH and FSH surges, which suggests that endogenous SP normally has an inhibitory role during this time.