In vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), a selective brain penetrant small molecule antagonist of the neuropeptide Y Y2 receptor

Shoblock, James R.; Welty, Natalie; Nepomuceno, Diane; Lord, Brian; Aluisio, Leah; Fraser, Ian; Motley, S. Timothy; Sutton, Steve W.; Morton, Kirsten L.; Galici, Ruggero; Atack, John; Dvorak, Lisa; Swanson, Devin M.; Carruthers, Nicholas I.; Dvorak, Curt A.; Lovenberg, Timothy W.; Bonaventure, Pascal

doi:10.1007/s00213-009-1726-x

Cited by 47 publications

(49 citation statements)

References 35 publications

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“…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.…”

Section: Npy Therapeutics Treatment Optionsmentioning

confidence: 99%

Neuropeptide Y and posttraumatic stress disorder

2012

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Section: Npy Therapeutics Treatment Optionsmentioning

confidence: 99%

Neuropeptide Y and posttraumatic stress disorder

2012

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“…A further NPY2-R antagonist described by Seierstad et al [125] and further characterized by Shoblock et al [51], JNJ-31020028 (21) (Figure 4), possessed a high selectivity, an affinity close to that of BIIE-0246 [126] between 6 and 9 nM and a Hill coefficient of 1. Investigations with this ligand provided evidence that NPY2-Rs play rather a modulating role, but not a pivotal one in the occurrence of preponderance and obesity.…”

Section: Non-peptide Ligands Of Npy Receptorsmentioning

confidence: 87%

“…Some of those have been radio-labeled for in vivo imaging. Clinical trials have been performed for ligands at CRF1 receptors [39,[42][43][44][45][46][47], at orexin receptors [48,49], at the NPY receptors [50,51], the opioid receptors [52], melanocortin -4-receptors (MC4-R) [53][54][55], melanin concentrating hormone receptors (MCH1-R) [56] and growth hormone secretagogue receptor 1 (ghrelin; GHS1-R) [57,58].…”

Section: Hypothalamus As a Potential Target For Drug Development In Tmentioning

confidence: 99%

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Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Pissarek¹,

Disko²

2013

WJNS

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Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants < 0.5 nM, partition coefficients log P < 3.5 and transcellular transport ratios, e.g. for the permeability glycoprotein transporter, below 3. Nevertheless, a multitude of compounds has been reported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of "feeding receptors" at the interface between neuroendocrine and mental diseases.

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“…In rats, injection of Y2 receptor antagonist BIIE 0246 into the hypothalamic arcuate nucleus (ARC) blocked the anorexic response to intraperitoneal (ip) injection of PYY and increased food intake in sated rats when administered alone during the light period, yet had no effect on feeding when administered at dark onset (2). Food intake also was not changed when either Y2 receptor antagonist BIIE 0246 or JNJ-31020028 was injected systemically at a dose that blocked PYY(3-36)-induced anorexia (38,41,44). It is not clear why these discrepancies occurred.…”

mentioning

confidence: 99%

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

Reidelberger

Haver

Chelikani

2013

American Journal of Physiology-Endocrinology and Metabolism

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Reidelberger R, Haver A, Chelikani PK. Role of peptide in the satiety produced by gastric delivery of macronutrients in rats. Am J Physiol Endocrinol Metab 304: E944 -E950, 2013. First published March 12, 2013 doi:10.1152/ajpendo.00075.2013 ] is postulated to act as a hormonal signal from gut to brain to inhibit food intake. PYY(3-36) potently reduces food intake when administered systemically or into the brain. If action of endogenous PYY(3-36) is necessary for normal satiation to occur, then pharmacological blockade of its receptors should increase food intake. Here, we determined the effects of iv infusion of Y1, Y2, and Y5 receptor antagonists (BIBP 3226, BIIE 0246, CGP 71683) during the first 3 h of the dark period on food intake in non-food-deprived 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 casein hydrolysate and long-chain triglycerides, but not maltodextrin. Previous work showed that Y2 antagonist BIIE 0246 does not penetrate the blood-brain barrier. 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.PYY; Y receptor antagonists; BIIE 0246; protein; lipid; carbohydrate; food intake PEPTIDE YY (PYY), NEUROPEPTIDE Y (NPY), and pancreatic polypeptide (PP) comprise a family of structurally-related brain-gut peptides with diverse actions mediated by five known receptors (Y1, Y2, Y4, Y5, Y6) (27). PYY, a 36-amino acid peptide, is synthesized in the gastrointestinal tract as well as in the central and peripheral nervous systems (12,18,19,29). Endocrine cells of the ileum, colon, and rectum provide a major source of PYY (3). Food intake releases at least two major forms of PYY into the circulation: PYY(1-36) and PYY(3-36) (3,22). PYY(1-36) binds to Y1, Y2, Y4, and Y5 receptors; PYY(3-36) is a high-affinity ligand for Y2 receptors with low affinity for Y1 and Y5 receptors (25). Systemic administration of PYY(3-36) potently inhibits food intake in humans (6), monkeys (30), and rodents (6, 15); PYY(1-36) is an order of magnitude less potent in humans (42) and rats (15). Pharmacological blockade of Y2 receptors reverses the anorexic response to systemic administration of PYY(3-36) (2, 38, 44).Thus, gut PYY(3-36) has been postulated to act at Y2 receptors to produce satiety (2).If gut PYY(3-36) action at Y2 receptors is necessary for normal satiation to occur, then food intake should increase in response to knockout of either the PYY gene or Y2 receptor gene or to pharmacological blockade of Y2 receptors. Germline deletion of the PYY gene increased food intake, however, in just...

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In vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), a selective brain penetrant small molecule antagonist of the neuropeptide Y Y2 receptor

Abstract: These results suggest that Y(2) receptors may not be critical for acute behaviors in rodents but may serve modulatory roles that can only be elucidated under specific situational conditions.

Cited by 47 publications

References 35 publications

Neuropeptide Y and posttraumatic stress disorder

Neuropeptide Y and posttraumatic stress disorder

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

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

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