The seminal finding that the M1/M4-preferring muscarinic acetylcholine receptor (mAChR) agonist xanomeline demonstrated robust antipsychotic efficacy in schizophrenia patients generated a major interest in developing selective M1 and M4 agonists and understanding the roles of these receptors. Unfortunately, all known mAChR agonists are non-selective and activate peripheral M2 and M3 receptors, leading to adverse effects. By targeting allosteric sights on mAChRs, we and others have succeeded in identifying highly subtype-selective positive allosteric modulators (PAMs) of individual mAChR subtypes that avoid activation of peripheral mAChRs. Interestingly, highly selective M4 PAMs have robust antipsychotic-like effects in multiple rodent models as well as cognition. However, M4 PAMs have progressed more slowly for many reasons, including species differences in M4 PAM potency (i.e., affinity and cooperativity), challenges with respect to M2 selectivity, and P-gp efflux as well as limited chemical diversity. Clearly, these are significant roadblocks en route to an M4 PAM preclinical candidate. In this talk, I will detail our navigation of these issues within the VU0467154 series of M4 PAMs, leading to the discovery of a potent, selective, and orally bioavailable M4 PAM VU0467485/AZ13713945 with robust efficacy in behavioral models that was evaluated as a preclinical candidate., While the mechanisms by which M4 PAMs exert their behavioral effects are not entirely clear, these compounds reverse multiple in vivo effects of psychomotor stimulants that induce increases in extracellular dopamine. These studies raise the possibility that M4 PAMs may act by inhibiting DA release from midbrain DA neurons. However, the hypothesis that selective M4 PAMs inhibit DA release has not been directly tested. Surprisingly, both the sustained inhibition of DA release and antipsychotic-like behavioral effects induced by an M4 PAM were found to require intact endocannabinoid (eCB)-mediated CB2 cannabinoid receptor signaling. Taken together, these studies identify a novel signaling pathway through which activation of M4 receptors on SPNs dampens dopaminergic signaling and highlights the importance of this pathway to the antipsychotic-like efficacy observed with M4 PAMs.

Discovery, development, mechanisitic insights and therapeutic potential of M4 PAMs

254th National Meeting (2017)

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