Food intake inhibition and reduction in body weight gain in lean and obese rodents treated with GW438014A, a potent and selective NPY-Y5 receptor antagonist

Modulation of neuropeptide Y expression in adult mice does not affect feeding

“…The other caveat is that NPY depletion was incomplete, even after 9 weeks of Dox treatment; therefore, one could argue that residual NPY is sufficient to maintain feeding. The latter possibility seems remote, considering that NPY receptor antagonists, antibodies, and antisense methods (15)(16)(17)(18)(19)(20)(21)(22) have all produced transient effects on feeding, and it is unlikely that complete inhibition of NPY signaling was achieved with any of these methods. The transient effect of Dox treatment on body weight of Npy tet/tet mice relative to WT controls was independent of food consumption and occurred while NPY levels were greater than those in WT mice.…”

“…Injection of NPY or NPY-related peptides intracranially (either into the hypothalamus or cerebral ventricles) stimulates robust feeding (1)(2)(3)(4)(5)(6); conditions of energy deprivation (starvation) or increased energy demand (lactation) induce NPY expression in the hypothalamus (7,8); most genetic models of obesity exhibit hyperphagia and an increase in hypothalamic NPY levels (9)(10)(11)(12)(13); and various pharmacological treatments that enhance feeding are accompanied by an increase in NPY (14). In addition, various methods (antisense oligonucleotides, antibodies, or receptor antagonists) aimed at blocking NPY actions in the hypothalamus have been shown to inhibit feeding (15)(16)(17)(18)(19)(20)(21)(22). Moreover, there is anatomical and electrophysiological evidence that NPY neurons in the arcuate (ARC) region of the hypothalamus have direct inhibitory inputs onto proopiomelanocortin (POMC) cells that form part of the melanocortin-signaling pathway, which suppresses feeding (23).…”

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

“…In some knockout mice studies, we should be aware of the biological counter-responses that probably may occur in the hypothalamus where extremely redundant neural networks exist (Beck, 2001). With reference to the specific Y5 antagonists, there is a variety of results on their effects on NPY-induced hyperphagia from positive Daniels et al, 2002;Della-Zuana et al, 2004) to negative ones (Kanatani et al, 2000;Turnbull et al, 2002), for some of which the specificity of the compounds is doubtful DellaZuana et al, 2004). Our data showing partial inhibition in NPY model and complete inhibition in hPP model strongly suggest that orally administered FMS586 fulfills the prerequisite condition of central Y5 blockade.…”

“…The above findings have encouraged the pharmaceutical industry to develop Y5-selective antagonists as appetite suppressants and antiobesity drugs. Although a large number of reports on pharmacological profile of low-molecular weight Y5 antagonists have been published so far, no clear consensus exists regarding physiological significance of Y5 in natural feeding and exogenous NPY-induced feeding (Daniels et al, 2002;Turnbull et al, 2002;Della-Zuana et al, 2004). As for the effective compounds, there needs to be more intensive assessment of the specificity.…”

Heterogeneity of the neuropeptide Y (NPY) contractile and relaxing receptors in horse penile small arteries

“…Structure-activity relationships for the NPY receptors were initially established on the basis of the action of several analogues and fragments of NPY, PYY and PP. However, the development of highly selective nonpeptide NPY receptor antagonists, first for the Y 1 receptor (Doods et al, 1995), and more recently for the Y 5 (Daniels et al, 2002) and Y 2 (Doods et al, 1999) receptors, has allowed a more precise pharmacological characterization of the NPY receptor subtypes.…”