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

Q2 · MEDICINE

Article

Author: Kitamura, Koichi ; Kakui, Nobukazu

An abundance of data suggests a crucial role of neuropeptide Y (NPY) as an activator of the hypothamamo-pituitary-adrenal (HPA) axis. However, there is quite limited evidence regarding receptors that mediate this response. Here, we address the possibility that Y5 receptor subtype may be responsible for NPY-induced activation of HPA axis. For this purpose, the effects of an intracerebroventricular injection of Y5-selective agonist, [cPP1–7, NPY19–23, Ala31, Aib32, Gln34]-human pancreatic polypeptide (hPP), on circulating ACTH and corticosterone in conscious rats were evaluated. Central injection of hPP (100 pmol) produced significant increases in plasma ACTH and corticosterone compared with artificial cerebrospinal fluid, and previous treatment with a novel Y5-selective antagonist, FMS586 [3-(9-isopropyl-6,7,8,9-tetrahydro-5H-carbazol-3-yl)-1-methyl-1-(2-pyridin-4-yl-ethyl)-urea hydrochloride] (25 mg/kg, po), completely blocked these alterations. Pretreatment with corticotropin-releasing factor (CRF) receptor antagonist (astressin, 10–50 μg/rat, iv) or arginine vasopressin (AVP) receptor antagonist ([deamino-Pen1, O-Me-Tyr2, Arg8] vasopressin; 3–30 μg/rat, iv) differentially suppressed these increases by 70–80 or 40–50%, respectively. The combined treatment showed no additive effect of these antagonists. Furthermore, an exogenous AVP (0.3 μg/rat, iv)-induced HPA activation was fully inhibited by astressin, suggesting a convergent pathway of AVP receptor signals onto CRF neurons. Central injection of hPP also evoked marked up-regulation of mRNA expression for CRF and AVP in the hypothalamus, which, likewise, were completely reversed by FMS586. Our observations provide the first evidence that selective stimulation of Y5 receptor provokes activation of the HPA axis and its downstream pathway is chiefly composed of both CRF (primary regulator) and AVP (subordinate to the former) with distinct relative contribution.

01 May 2006·Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Asai, Kenji ; Suzuki, Makoto ; Sugai, Masaharu ; Miyara, Takako ; Masuda, Naomi ; Kitaguchi, Hiroshi ; Kakui, Nobukazu ; Nishikawa, Naoyuki ; Nakatani, Yuko ; Aoki, Kozo ; Ohsawa, Fukuichi ; Tabata, Yuji ; Tanaka, Jiro

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) = 4.3 +/- 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 gamma-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.

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Indication	Highest Phase	Country/Location	Organization	Date
Obesity	Discovery	JP	Meiji Seika Pharma Co., Ltd.	-

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