WAY‐131256 is an orally active, efficacious, and in vivo functionally selective M1 agonist

Abstract

Computer modeling of carbachol docked in the human m1 receptor binding pocket has been used to discover a series of carbamate and thiocarbamate 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 (m1–m5) transfected into a CHO cell line. None of these compounds was selective in binding. Thiocarbamate analogues had greater affinity for the m1 receptor subtype, but lower efficacy based on comparison of their ability to induce phosphoinositide (PI) turnover. Carbamate analogues had lower affinity for m1 receptors than thiocarbamates and varied in efficacy from 10% to 100% of the carbachol response in phosphoinositide (PI) turnover. One of these analogues 3S,4R‐azabicyclo[2.2.1]heptan‐3‐methylcarbamate, WAY‐131256, (VI) has been characterized as an m1/m2 agonist in vitro. (VI) was equi‐efficacious to the standard m1 agonist, xanomeline (Phase III) in vivo in a scopolamine‐impaired radial arm 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 m1 selectivity in vitro, in vivo experiments on (VI) indicated no significant 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 m2 or m3 receptors (salivation, lacrimation, and chromodacryorrhea) up to doses of 30 mg/kg, 176.2 mmol/kg. These results may be explained by different receptor densities in various brain regions not accounted for in a transfected cell line or by metabolism of (VI) to a m1 selective agonist in vivo. Drug Dev. Res. 40:185–192, 1997. © 1997 Wiley‐Liss, Inc.

Therapeutic Opportunities for Muscarinic Receptors in the Central Nervous System

“…WAY-131256 (20), a rigid carbamate analogue of acetylcholine, does not show selective affinity among the M 1 -M 5 receptor subtypes, and 20 is comparably potent agonist at both M 1 and M 2 receptors. 90 By contrast, in vivo studies suggested that 20 is selective for M 1 receptors compared to M 2 and M 3 receptors. Thiadiazole ester bioisosteres of aceclidine (21a,b) are as comparably efficacious and potent as the functionally selective M 1 agonist xanomeline (11b) in an M 1 cell line and have very little M 3 activity in vivo.…”

“…Functional assays demonstrate that 19 is an agonist at M 1 −M 4 receptors but only a partial agonist at M 3 receptors. WAY-131256 ( 20 ), a rigid carbamate analogue of acetylcholine, does not show selective affinity among the M 1 −M 5 receptor subtypes, and 20 is comparably potent agonist at both M 1 and M 2 receptors . By contrast, in vivo studies suggested that 20 is selective for M 1 receptors compared to M 2 and M 3 receptors.…”