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

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 [¹²⁵I]­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 (<b>2</b>) had an IC₅₀ = 62 nM and displayed excellent oral bioavailability in rat (% <i>F</i> po = 80), as well as good brain penetration (B/P ratio = 0.61). In a spontaneous nocturnal feeding study with male Sprague–Dawley rats, <b>2</b> significantly reduced food intake during a 12 h period