WAY-131256 IS AN ORALLY-ACTIVE, EFFICACIOUS, AND IN-VIVO FUNCTIONALLYSELECTIVE M-1 AGONIST

Computer modeling of carbachol docked in the human m(1) receptor bindi ng pocket has been used to discover a series of carbamate and thiocarb amate chiral, conformationally restricted analogues of carbachol based on azabicyclo[2.2.1]heptan-3-ol. These molecules have been evaluated for affinity and efficacy at human muscarinic receptors (m(1)-m(5)) tr ansfected into a CHO cell line. None of these compounds was selective in binding. Thiocarbamate analogues had greater affinity for the m(1) receptor subtype, but lower efficacy based on comparison of their abil ity to induce phosphoinositide (PI) turnover. Carbamate analogues had lower affinity for mi receptors than thiocarbamates and varied in effi cacy from 10% to 100% of the carbachol response in phosphoinositide (P I) turnover. One of these analogues 3S,4R-azabicyclo[2.2.1]heptan-3-me thylcarbamate, WAY-131256, (VI) has been characterized as an m(1)/m(2) agonist in vitro. (VI) was equi-efficacious to the standard m(1) agon ist, xanomeline (Phase III) in vivo in a scopolamine-impaired radial a rm maze paradigm (MED 1 mg/kg, 5.88 mmol/kg for VI and MED 1 mg/kg, 3. 55 mmoles/kg for xanomeline) and was approximately equal to xanomeline in an AF64A-impaired radial arm maze paradigm. Despite its lack of m( 1) selectivity in vitro, in vivo experiments on (VI) indicated no sign ificant effect on blood pressure or heart rate at 10 mg/kg (58.78 mmol /kg) (i.p.), and no peripheral side effects attributed to stimulation of either the mt or m(3) receptors (salivation, lacrimation, and chrom odacryorrhea) up to doses of 30 mg/kg, 176.2 mmol/kg. These results ma y be explained by different receptor densities in various brain region s not accounted for in a transfected cell line or by metabolism of (VI ) to a m(1) selective agonist in vivo. (C) 1997 Wiley-Liss, Inc.