Knockout (KO) mice of the muscarinic acetylcholine receptor (mAChR) subtype M5 have revealed the receptor’s role in a multitude of CNS processes. Animals lacking this receptor have demonstrated decreased dilation of vasculature in response to acetylcholine (ACh), leading to cognitive deficits and highlighting the possible involvement of M5 in various CNS disorders including Alzheimer’s disease (AD) and ischemic stroke. M5 is currently the least characterized of the mAChR subtypes, due largely in part to its relatively low expression level in the CNS and lack of subtype selective tool compounds. Building on the recent optimization of potent and selective M5 positive allosteric modulators (PAMs) featuring a N-benzyl-1-(phenylsulfonyl)piperidine-4-carboxamide structure, we report here a constrained series of chiral indane analogs with superior potency (and subtype selectivity) for M5, and demonstrate enantiopreference for the (R)-indane analogs in this series. Despite some PAM activity at the other mAChR subtypes, these second generation M5 compounds were demonstrated to bind M5 allosterically in [3H]-NMS radioligand binding assays, and additional in vitro pharmacological characterization has demonstrated a unique positive cooperativity profile with the other mAChRs.

Synthesis and characterization of a highly potent series of substituted N-(indanyl)piperidine-4-carboxamides as positive allosteric modulators of the M5 muscarinic acetylcholine receptor

255th National Meeting (2018)

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