Taltirelin

Teratogenicity study of taltirelin hydrate, a thyrotropin releasing hormone analogue, was carried out in Wistar rats. Female rats were orally given taltirelin hydrate at a dose of 0 (control), 0.15, 1.5, or 15 mg/kg from day 7 to day 17 of gestation. Twenty-seven female rats in each group were sacrificed on day 21 of gestation and their fetuses were examined. The remaining 13 female rats in each group were allowed to deliver spontaneously and their newborns were examined. In the 15 mg/kg group, the dams (P) showed wet dog shaking behavior and hyperlocomotion. No adverse effect of taltirelin hydrate on the body weight gain, food consumption, water intake, and reproductive performance was observed in this group. In the 0.15 and 1.5 mg/kg groups, taltirelin hydrate did not show any adverse effects. In F1 generation groups, taltirelin hydrate had no teratogenic, lethal, or growth retardation effects in any groups. There were also no adverse effects of taltirelin hydrate on postnatal development, emotionality, coordinated activity, sensitivity, learning ability, and reproductive performance of F1 offspring, and development of F2 fetuses. These results show that the no-toxic dose levels of taltirelin hydrate are 1.

Sites and mechanisms of the antagonistic action of TA-0910, a new thyrotropin-releasing hormone (TRH) analog, on pentobarbital anesthesia were studied in rats. Intravenous administration of TA-0910 dose-dependently shortened the duration of pentobarbital anesthesia at 30 micrograms/kg or more. The anti-anesthetic action of TA-0910 after intracerebral injection was in the following order of effectiveness: the posterior lateral hypothalamic area greater than midbrain reticular formation greater than raphe nuclei = locus ceruleus greater than anterior lateral hypothalamic area = ventral globus pallidus = hippocampus. TA-0910 injected into the nucleus accumbens, medial septal nucleus, parietal cortex or striatum had no effect, even at high doses. The anti-anesthetic action of TA-0910 (0.1 mg/kg, i.v.) was inhibited by a low dose of scopolamine or mecamylamine and by a high dose of haloperidol, phenoxybenzamine or metergoline. However, physostigmine and oxotremorine showed no anti-anesthetic action alone or in combination with TA-0910 (0.01 mg/kg, i.v.). Pentobarbital anesthesia was not inhibited by carbachol injected into various sites of the brain. These results suggest that the inhibitory effect of TA-0910 on pentobarbital anesthesia is mainly produced by activation of the posterior lateral hypothalamic area and the midbrain reticular formation, and that the involvements of not only acetylcholine but also other neurotransmitters such as dopamine, serotonin, and noradrenaline should be examined for their anti-anesthetic action.

Thyrotropin-releasing hormone (TRH) receptor binding in the rat brain after intravenous (i.v.) injections of novel TRH analogues, taltirelin and montirelin, was examined and the data were analyzed in relation to their plasma concentrations which were simultaneously determined. Taltirelin and montirelin inhibited specific [3H]-Me-TRH binding in the rat brain and their Ki values were 311 and 35.2 nM, respectively. The i.v. injection of taltirelin and montirelin (0.1-3 mg/kg) produced a significant reduction in [3H]-Me-TRH binding sites (Bmax values) in the rat brain. The reduction by both agents tended to reach a maximum after 60 min and lasted up to at least 120 min. On the other hand, the i.v. injection of both agents had little significant effect on the apparent dissociation constant (Kd) for [3H]-Me-TRH in the rat brain. Plasma concentrations of taltirelin and montirelin in rats peaked immediately after i.v. injection, and thereafter they decreased with t 1/2 of 23.0 and 14.1 min, respectively. Counter-clockwise hysteresis between the plasma concentration and receptor occupancy of these agents was observed after the i.v. injection of taltirelin and montirelin, and the temporal delay between plasma concentration and brain receptor occupancy was successfully minimized using the "effect compartment" model in combination with the "linear-effect" model.