Contrasting pharmacodynamic requirements of disease models revealed through characterization of a novel and selective M1 agonist

Abstract

A new class of selective M1 muscarinic allosteric agonists has emerged. Reported here, is the in vitro and in vivo characterization of a novel M1 agonist, PPBI, a new member of that family and the clear demonstration that the biological effects of PPBI are mediated through M1. PPBI reverses d‐amphetamine locomotor activity, but fails to do so in transgenic mice that do not express M1. At much lower doses, PPBI reverses a natural deficit in a rat cognition model, occurring at an exposure level which is also shown to activate cortical circuitry as measured by phMRI. Most importantly, PPBI is analgesic in a variety of rat and mouse models and the analgesic effect of PPBI is reversed by an M1‐preferring antagonist and an M1‐selective toxin. Finally, the pharmacokinetic/pharmacodynamic measures of this highly characterized tool are compared across multiple endpoints and it is concluded that models of psychosis and pain require greater M1 receptor activation by PPBI than that required in the cognition model.