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

Autor: Rene P. Tasse, Carl A. Boast, Annmarie Louise Sabb, Deepa Malhotra, Herman Morris, Denise Fairman, Reinhardt P. Stein, Magid Abou-Gharbia, Adam C. Bartolomeo, Tracy Sailer, Douglas M. Ho, John A. Moyer, Robert Lewis Vogel, Susan Amburn, Dianne Kowal
Rok vydání: 1997
Předmět:
Zdroj: Drug Development Research. 40:185-192
ISSN: 1098-2299
0272-4391
DOI: 10.1002/(sici)1098-2299(199702)40:2<185::aid-ddr8>3.0.co;2-h
Popis: Computer modeling of carbachol docked in the human m 1 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 (m 1 -ms) transfected 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 ability to induce phosphoinositide (PI) turnover. Carbamate analogues had lower affinity for m 1 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 m 1 /m 2 agonist in vitro. (Vl) was equi-efficacious to the standard m i 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 m 1 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 m 2 or m 3 receptors (salivation, lacrimation, and chromodacryorrhea) up to doses of 30 mg/kg, 1 76.2 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 m 1 selective agonist in vivo.
Databáze: OpenAIRE
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