Highly Selective and Potent Neuropeptide Y (NPY) Y1 Receptor Antagonists Based on [Pro³⁰, Tyr³², Leu³⁴]NPY(28-36)-NH₂ (BW1911U90)

Identification of a Cyanine-Dye Labeled Peptidic Ligand for Y1R and Y4R, Based upon the Neuropeptide Y C-Terminal Analogue, BVD-15

“…It did not bind cells expressing Y2R or Y5R (data not shown) at up to 1 µM, as might be predicted from the reported selectivity profile for BVD-15. 35 In contrast to its actions at the Y1R, H was a Y4R partial agonist, a property shared by BVD-15, in the β-arrestin2 recruitment assay (Figure 6; pEC50 = 7.10 ± 0.19, 1 µM response 59.0 ± 3.6 %, 100 nM PP, n = 6); other cyanine BVD-15 analogues E-G displayed limited Y4R agonism at the highest concentration tested (1 µM). At 100 nM, H selectively labelled 293TR cells expressing Y4R-GFP (Figure 6A), enabling competition binding studies to derive pKi estimates for human PP, 1229U91 and its analogues I and J ( Figure 6C; Table 4).…”

Induction of Hypertrophic Responsiveness of Cardiomyocytes to Neuropeptide Y in Response to Pressure Overload

“…Although the potent activity of WX-143B, which is incompatible with an action via any other Y receptor subtype ( Table 2), indicates that NPY Y 4 receptors could also be linked to a hypertrophic pathway, it is very unlikely that NPY Y 4 receptors would mediate the hypertrophic response to NPY in vivo, because the endogenous peptide has very low affinity for Y 4 receptors ( Table 2; Gregor et al, 1996). In addition, BVD-42 (2 ϫ 10 Ϫ7 M) did not attenuate the action of NPY, although the majority of Y 4 receptors would have been blocked at this concentration (K i value Y 4 receptor ϭ 6.5 ϫ 10 Ϫ8 M; Balasubramaniam et al, 2001). In contrast to the declining response to NPY (Ͼ10 nM) at 16 weeks (Fig.…”

“…[Leu 31 Pro 34 ]-NPY is an agonist with high affinity for NPY Y 1 , Y 4 , and Y 5 receptors but devoid of activity at NPY Y 2 receptors, whereas peptide YY ) is selective for NPY Y 2 and NPY Y 5 receptors relative to other NPY Y receptor subtypes (Michel et al, 1997). ]-NPY (Parker et al, 2000) and [Ala 31 ,Aib 32 ]-NPY are potent and selective NPY Y 5 receptor agonists, whereas WX-143-B is a highly selective agonist at NPY Y 4 receptors (Balasubramaniam et al, 2001). More recently, development of nonpeptide NPY Y receptor antagonists has assisted greatly in receptor classification .…”

“…More recently, development of nonpeptide NPY Y receptor antagonists has assisted greatly in receptor classification . BVD-42 is a selective antagonist at NPY Y 1 receptors (Balasubramaniam et al, 2001), whereas BIIE0246 is a selective antagonist at NPY Y 2 receptors (King et al, 2000). Availability of such compounds provides opportunity for reevaluation of the NPY Y receptor subtypes present in ventricular myocardium.…”

Neuropeptide Y Receptor Selective Ligands in the Treatment of Obesity

“…In a study (208) using both Y 1 (120562A, BIBO 3304) and Inhibited spontaneous food intake, fasted food intake, freefeeding or NPY-induced feeding in rats (162)(163)(164)(165)(166)(167)(168)(169)(170)(171)(172)(173)(174)(175) Y 5 receptor 2-͓4-(8-methyl-2-oxo-4H-benzo͓d͔͓1,3͔oxazin-1-yl)piperidin-1-yl͔-N-(9-oxo-9H-fluoren-3-yl)acetamide 5p (188), CGP 71683A (197)(198)(199) Inhibited spontaneous food intake, fasted food intake, freefeeding rats or NPY-induced food intake in rats (188,197,198) and guinea pigs (199) GW438014A (200) FMS586 (201) Decreased weight gain rate and fat mass in rodents (200), induced acute and robust feeding responses in satiated rats (201) NPY5RA-972 (209,210) No effect on NPY-induced feeding (209, 210) Compound (Ϫ)-7, (features 2,3-dihydro-1H-yclopenta͓a͔naphthalene moiety͔ (202) Inhibited Y 5 agonist bovine PP-induced food intake in rat, no effect on NPY-induced feeding (202) JCF 104, JCF 109 (208) Reduced hyperphagic effect of NPY (208) ͓cPP1-7, NPY19 -23, Ala31,Aib32, Q34͔hPP (215) Stimulated food intake in rats (215) (199). Interestingly, the effect of the antagonists tended to cause different feeding behavior.…”