Selective and Brain Penetrant Neuropeptide Y Y2 Receptor Antagonists Discovered by Whole-Cell High-Throughput Screening

Abstract

The role of neuropeptide Y Y2 receptor (Y2R) in human diseases such as obesity, mood disorders, and alcoholism could be better resolved by the use of small-molecule chemical probes that are substantially different from the currently available Y2R antagonist,Presented here are five potent, selective, and publicly available Y2R antagonists identified by a high-throughput screening approach. These compounds belong to four chemical scaffolds that are structurally distinct from the peptidomimetic BIIE0246. In functional assays, IC 50 values between 199 and 4400 nM against the Y2R were measured, with no appreciable activity against the related NPY-Y1 receptor (Y1R). Compounds also displaced radiolabeled peptide YY from the Y2R with high affinity (K i values between 1.55 and 60 nM) while not displacing the same ligand from the Y1R. In contrast to BIIE0246, Schild analysis with NPY suggests that two of the five compounds behave as competitive antagonists. Profiling against a panel of 40 receptors, ion channels, and transporters found in the central nervous system showed that the five Y2R antagonists demonstrate greater selectivity than BIIE0246. Furthermore, the ability of these antagonists to penetrate the blood-brain barrier makes them better suited for pharmacological studies of Y2R function in both the brain and periphery.Neuropeptide Y (NPY) is one of the most abundant neuropeptides in the mammalian brain (Catapano and Manji, 2007) and was originally identified in 1982 based on its structural similarity to peptide YY (70% homology with PYY) and pancreatic polypeptide (50% homology with PP) (Tatemoto, 1982). Each of these 36-residue peptides is processed from a 94-to 95-residue prohormone (Balasubramaniam, 1997). Four related type 1 G protein-coupled receptor (GPCR) family members (Y1, Y2, Y4, and Y5) mediate biological responses to NPY. These receptors couple to the G␣ i signaling pathway and inhibit adenylate cyclase, preventing cAMP production.Although NPY receptors have mainly been of interest to the pharmaceutical industry as therapeutic targets for obesity and feeding disorders, NPY has numerous roles in the body, including modulation of feeding behavior, circadian rhythm,

Role of peptide YY(3–36) in the satiety produced by gastric delivery of macronutrients in rats

“…Our results showed that 1) Y2 receptor blockade reversed the anorexic response to iv infusion of PYY(3-36) but did not increase food intake when administered alone; 2) Y1 and Y5 receptor antagonists neither attenuated PYY(3-36)-induced anorexia nor altered food intake when given alone; and 3) Y2 receptor blockade attenuated anorexic responses to gastric infusions of lower doses of casein hydrolysate and long-chain triglycerides but not to maltodextrin infusions. Previous work showed that Y2 antagonist BIIE 0246 does not penetrate the blood-brain barrier (13). Together, these results support the hypothesis that gut PYY(3-36) action at Y2 receptors peripheral to the blood-brain barrier plays an essential role in mediating satiety responses to gastric delivery of protein and long-chain triglycerides but not polysaccharide.…”

“…The present study further supports this hypothesis. Intravenous infusion of Y2 receptor antagonist BIIE 0246, which does not readily penetrate the blood-brain barrier (13), attenuated anorexic responses to iv infusion of PYY and to gastric infusions of casein hydrolysate and long-chain triglycerides but not maltodextrin. Together, these results suggest that gut PYY(3-36) action at Y2 receptors peripheral to the blood-brain barrier plays an essential role in mediating satiety responses to gastric delivery of protein and long-chain triglycerides but not polysaccharide.…”

Blockage of Peripheral NPY Y1 and Y2 Receptors Modulates Barorefex Sensitivity of Diabetic Rats

“…Based on the results, we hypothesized that the elevated plasma NPY might negatively influences BRS and cardiac function via activation of Y1R and Y2R in DM. With the consideration that they could not cross the blood brain barrier, we employed BIBP 3226 and BIIE 0246 as Y1R and Y2R antagonists respectively [26,27]. Based on the essential role of lipid metabolism in cardiovascular dysfunction of DM, we measured the plasma lipid concentration and found that BIBP 3226 and BIIE 0246 rescued the aberrant lipid level.…”

Neuropeptide Y and posttraumatic stress disorder

“…Current therapeutic options are: (i) intranasal NPY delivery: to circumvent degradation in the gastrointestinal tract and to deliver peptide directly to the CNS; and (ii) novel blood-brain barrier penetrant nonpeptide Y2 antagonists that are currently being developed and tested. [165][166][167] The clinical utility and potential adverse effect profiles remain to be determined. Thus, there is a critical need for collaborative efforts in this area for design, development and preclinical testing of new agents as they become available.…”