Pharmacological Characterization and Feeding-Suppressive Property of FMS586 [3-(5,6,7,8-Tetrahydro-9-isopropyl-carbazol-3-yl)-1-methyl-1-(2-pyridin-4-yl-ethyl)-urea Hydrochloride], a Novel, Selective, and Orally Active Antagonist for Neuropeptide Y Y5 Receptor

Abstract

We evaluated the pharmacological profiles of FMS586 [3-(5,6,7,8-tetrahydro-9-isopropyl-carbazol-3-yl)-1-methyl-1-(2-pyridin-4-yl-ethyl)-urea hydrochloride], a novel tetrahydrocarbazole derivative as a neuropeptide Y (NPY) Y5 receptor antagonist. This compound showed a highly selective in vitro affinity for Y5 (IC 50 ϭ 4.3 Ϯ 0.4 nM) relative to other NPY receptor subtypes like Y1 or Y2. Its binding to Y5 was found to be fully antagonistic from cyclic AMP accumulation assays in human embryonic kidney 293 cells. Pharmacokinetic analysis revealed sufficient oral availability and brain permeability of this compound accompanied with clear dose relation. We attempted to assess the selectivity of FMS586 and, thereby, to infer the physiological role of Y5 in the following feeding experiments in normal rats. An intracerebroventricular injection of NPY and Y5-selective agonist peptide induced acute and robust feeding responses in satiated rats, and prior administration of FMS586 at the doses from 25 to 100 mg/kg clearly inhibited these responses by approximately 55 and 90%, respectively. This compound also showed dose-dependent but transient suppression in natural feeding models of both overnight fasting-induced hyperphagia and spontaneous daily intake. FMS586 did not modulate food intake induced by the topical injection of norepinephrine, galanin, or ␥-aminobutyric acid receptor agonist muscimol to the paraventricular nucleus. In addition, we confirmed the Y5-specific activity profile of FMS586 by immunohistochemical analysis. Taken together, we propose not only that our compound potentially expresses specific blockade of central Y5 signals but also that Y5 receptor would certainly contribute to physiological regulation of food intake in normal rats, as suggested from its origin.

Direct Evidence that Stimulation of Neuropeptide Y Y5 Receptor Activates Hypothalamo-Pituitary-Adrenal Axis in Conscious Rats via both Corticotropin-Releasing Factor- and Arginine Vasopressin-Dependent Pathway

“…1, A and B). We reported previously that the same dosing of hPP induces hyperphagic response in satiated rats (21). In that study, the minimal effective dose of FMS586 was shown to be 25 mg/kg (po).…”

“…FMS586 was synthesized at Ashigara Research Laboratories of Fuji Photo Film (Kanagawa, Japan) (21). Human/rat CRF and AVP were obtained from Peptide Institute Inc. (Osaka, Japan).…”

“…The purpose of this experiment was to examine the activation of HPA axis in response to central administration of the Y 5 -selective agonist hPP and to evaluate the antagonistic effect of FMS586 to such stimulation. The doses of the agonist (100 pmol, icv) and the antagonist (25 mg/kg, po) were shown to be valid for substantial activation and sufficient inhibition of Y 5 receptor function (21). Rats were randomly divided into four groups and orally given either FMS586 or its vehicle (0.1 mN HCl as an acidity-matched control).…”

“…Rats were anesthetized with pentobarbital (50 mg/kg, ip) and implanted with a permanent 25-gauge stainless steel guide cannula (Eicom, Kyoto, Japan). The stereotaxic coordinates were Ϫ0.8 mm posterior to the bregma, 1.5 mm lateral to the midline, and 3.5 mm ventral from the skull surface (21). Rats were allowed to recover for more than 7 d until the next surgery.…”

The Novel Neuropeptide Y Y5 Receptor Antagonist Lu AA33810 [N-[[trans-4-[(4,5-Dihydro[1]benzothiepino[5,4-d]thiazol-2-yl)amino]cyclohexyl]methyl]-methanesulfonamide] Exerts Anxiolytic- and Antidepressant-Like Effects in Rat Models of Stress Sensitivity

“…MK-0557 is a high-affinity Y 5 receptor antagonist (rat Y 5 K i ϭ 1.4 nM) that recently produced a small but statistically significant reduction in body weight in clinical trials of obese human subjects (Erondu et al, 2006). Additional examples include L-152,804 (rat Y 5 K i ϭ 31 nM) (Kanatani et al, 2000) and (Kakui et al, 2006). The use of these and other antagonists has contributed to our view of how the Y 5 receptor may regulate metabolism under various conditions and in multiple species.…”