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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

Shoblock, James R., Welty, Natalie, Nepomuceno, Diane, Lord, Brian, Aluisio, Leah, Fraser, Ian, Motley, S. Timothy, Sutton, Steve W., Morton, Kirsten, Galici, Ruggero, Atack, John R., Dvorak, Lisa, Swanson, Devin M., Carruthers, Nicholas I., Dvorak, Curt, Lovenberg, Timothy W. and Bonaventure, Pascal 2010. 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. Psychopharmacology 208 (2) , pp. 265-277. 10.1007/s00213-009-1726-x

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Rationale The lack of potent, selective, brain penetrant Y2 receptor antagonists has hampered in vivo functional studies of this receptor. Objective Here, we report the 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 novel Y2 receptor antagonist. Methods The affinity of JNJ-31020028 was determined by inhibition of the PYY binding to human Y2 receptors in KAN-Ts cells and rat Y2 receptors in rat hippocampus. The functional activity was determined by inhibition of PYY-stimulated calcium responses in KAN-Ts cells expressing a chimeric G protein Gqi5 and in the rat vas deferens (a prototypical Y2 bioassay). Ex vivo receptor occupancy was revealed by receptor autoradiography. JNJ-31020028 was tested in vivo with microdialysis, in anxiety models, and on corticosterone release. Results JNJ-31020028 bound with high affinity (pIC50 = 8.07 ± 0.05, human, and pIC50 = 8.22 ± 0.06, rat) and was >100-fold selective versus human Y1, Y4, and Y5 receptors. JNJ-31020028 was demonstrated to be an antagonist (pKB = 8.04 ± 0.13) in functional assays. JNJ-31020028 occupied Y2 receptor binding sites (~90% at 10 mg/kg) after subcutaneous administration in rats. JNJ-31020028 increased norepinephrine release in the hypothalamus, consistent with the colocalization of norepinephrine and neuropeptide Y. In a variety of anxiety models, JNJ-31020028 was found to be ineffective, although it did block stress-induced elevations in plasma corticosterone, without altering basal levels, and normalized food intake in stressed animals without affecting basal food intake. Conclusion These results suggest that Y2 receptors may not be critical for acute behaviors in rodents but may serve modulatory roles that can only be elucidated under specific situational conditions.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Springer Verlag (Germany)
ISSN: 0033-3158
Date of Acceptance: 6 November 2009
Last Modified: 14 Nov 2017 15:08

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