Consistent with the hypothesized therapeutic impact of mACh receptor activation is a small clinical trial in schizophrenia showing antipsychotic efficacy of the putative M1/M4 selective mACh receptor agonist xanomaline.185 Current cholinergic

therapeutics are limited in their applicability because of aversive side-effect profiles that are attributed to peripheral activation of M2 and M3 mACh receptors.186,187 For this reason, Inhibitors,research,lifescience,medical the development of subtype selective ligands has been a major interest. M1 and M4 subtypes are of greatest interest in schizophrenia, given the efficacy of xanomaline (an M1/M4-pref erring agonist) and postmortem findings of reduced M1 and M4 receptor densities in schizophrenia.188,189 Studies with mutant mice support the targeting of M1 and M4 receptors. Null deletion mutants of M1 receptors display deficits in working memory and social memory,190 as well as elevated baseline dopamine turnover and increased sensitivity to the behavioral and neurochemical effects of amphetamine.191 Inhibitors,research,lifescience,medical Likewise M4 null mutant mice display hypersensitivity to amphetamine and PCP-induced increases in nucleus acccumbens dopamine, consistent with an involvement of NMDA receptors.192 In the Rigosertib chemical structure absence of selective pharmacological tools, mutant animal studies have been used to improve our understanding of the neurophysiological Inhibitors,research,lifescience,medical role of mACh receptors.187 M4 null mutant mice display enhanced baseline ACh efflux with in vivo dialysis

in various brain regions, consistent with a prominent role as an autoreceptor193 The finding that M1 null mutation abolishes ACh-mediated LTP of pyramidal neurons in the hippocampus194 complements earlier work suggesting a similar role for M1 receptors in the potentiation of NMDA receptor currents.195 Taken together, Inhibitors,research,lifescience,medical these Inhibitors,research,lifescience,medical studies suggest that M1 mACh receptors possess

activity similar to that of mGlu5 receptors, modulating NMDA receptor signaling postsynaptically mACh receptors, like mGluRs, have proven to be difficult to selectively target at the orthosteric site. The agonist xanomaline, though often touted as M1/M4-selective, possesses prominent affinity for other tuclazepam subtypes. Recent progress has been made in the development of M1 and M4 PAMs and allosteric agonists for mACh receptors.196 As with mGlu receptors, allosteric modulation appears to be a promising route for achieving pharmacological selectivity. Recent studies describe the activity of a M1-selective allosteric agonist, 1-(1′-2-methylbenzyl)-1,4′-bipiperidin4-yl)-1H-benzo[ d]imidazol-2(3H)-one (TBPB) and a PAM, benzylquinolone carboxylic acid (BQCA). In experiments that further elucidate the physiological roles of M1 receptors, TBPB enhances NMDA receptor currents; BQCA enhances the frequency and amplitude of spontaneous excitatory neurotransmission in the cortex.197 In evidence of in vivo activity, TBPB reduced amphetamineinduced hyperactivity198 and BQCA enhanced reversal learning in a murine transgenic model of Alzheimers’ disease.