It was hypothesized that selective muscarinic M1 activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer’s disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Recent data disputes this hypothesis by demonstrating that activation of the M1 receptor by subtype-selective positive allosteric modulators (PAMs) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M2 and M3 activation. These studies were completed using PAMs that also exhibited allosteric agonist activity leaving the possibility that direct agonism, rather than allosteric modulation, could be responsible.<br/>To test this hypothesis we compared the safety of three structurally distinct M1 PAMs with varying degrees of allosteric agonism. The potency of each compound was measured in mouse striatum using an ex-vivo inositol monophosphate (IP1) accumulation assay. Safety TI’s were calculated using the unbound compound concentration in the brain corresponding to a 2-fold increase of IP1 as the denominator. Holistically we found that the safety risks presented by all three ligands are similar, which suggests that convulsion and GI AE’s are not compound or chemotype specific.

Convulsion and cholinergic toxicity of subtype selective M<sub>1</sub> positive allosteric modulators (PAMs)

254th National Meeting (2017)

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Convulsion and cholinergic toxicity of subtype selective M1 positive allosteric modulators (PAMs)

Convulsion and cholinergic toxicity of subtype selective M₁ positive allosteric modulators (PAMs)