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Discovery of a Novel Class of Bicyclo[3.1.0]hexanylpiperazines as Noncompetitive Neuropeptide Y Y1 Antagonists.

ABSTRACT: A novel class of bicyclo[3.1.0]hexanylpiperazine neuropeptide Y (NPY) Y1 antagonists has been designed and synthesized. Scatchard binding analysis showed these compounds to be noncompetitive with [(125)I]PYY binding to the Y1 receptor. The most potent member, 1-((1?,3?,5?,6?)-6-(3-ethoxyphenyl)-3-methylbicyclo[3.1.0]hexan-6-yl)-4-phenylpiperazine (2) had an IC50 = 62 nM and displayed excellent oral bioavailability in rat (% F po = 80), as well as good brain penetration (B/P ratio = 0.61). In a spontaneous nocturnal feeding study with male Sprague-Dawley rats, 2 significantly reduced food intake during a 12 h period.

SUBMITTER: Hu S

PROVIDER: S-EPMC4025839 | biostudies-other | 2012 Mar

REPOSITORIES: biostudies-other

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Discovery of a Novel Class of Bicyclo[3.1.0]hexanylpiperazines as Noncompetitive Neuropeptide Y Y1 Antagonists.

Hu Shuanghua S Huang Yazhong Y Deshpande Milind M Luo Guanglin G Bruce Marc A MA Chen Ling L Mattson Gail G Iben Lawrence G LG Zhang Jie J Russell John W JW Clarke Wendy J WJ Hogan John B JB Ortiz Astrid A Flint Oliver O Henwood Andrew A Gao Qi Q Antal-Zimanyi Ildiko I Poindexter Graham S GS

ACS medicinal chemistry letters 20120104 3

A novel class of bicyclo[3.1.0]hexanylpiperazine neuropeptide Y (NPY) Y1 antagonists has been designed and synthesized. Scatchard binding analysis showed these compounds to be noncompetitive with [(125)I]PYY binding to the Y1 receptor. The most potent member, 1-((1α,3α,5α,6β)-6-(3-ethoxyphenyl)-3-methylbicyclo[3.1.0]hexan-6-yl)-4-phenylpiperazine (2) had an IC50 = 62 nM and displayed excellent oral bioavailability in rat (% F po = 80), as well as good brain penetration (B/P ratio = 0.61). In a s ...[more]

PMID: 24900458

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