The muscarinic acetylcholine receptors (mAChR) consist of five subtypes (M1-5) that are broadly expressed in the central nervous system and periphery of mammals. These receptors and their endogenous agonist, acetylcholine (ACh), play an important role in regulating a wide range of physiological functions. Recent advances in the discovery of highly subtype-specific ligands for M1 and M4 has enabled researchers to begin pharmacological characterization of the discrete functions of these subtypes; however, discovery of M5-selective ligands has remained challenging.Consistent with M5 expression in midbrain dopamine pathways and throughout the cerebrovascular system, phenotypic studies of M5-knockout mice have suggested that activation of M5 may be therapeutically relevant for the treatment of chronic cerebrovascular diseases, acute ischemic stroke, Alzheimer's disease, and drug addiction.We recently reported the discovery of the first subtype-selective M5 positive allosteric modulators (PAMs) based on ML129 (VU0238429; hM5 EC50 = 1.1 �M), but their modest potency and poor physiochemical profiles limit their in vivo utility as pharmacological probes and all attempts at further optimization were unsuccessful. A subsequent HTS campaign discovered several weak M5 PAMs structurally related to ML129, but with unique peripheral pharmacophores. Although these new compounds were unable to be optimized further, the juxtaposition of the peripheral pharmacophores with ML129's core resulted in a prodigious increase in potency, leading to the first sub-micromolar, M5-selective PAM, ML326 (VU0467903; hM5 EC50 = 409 nM).

Discovery of ML326: The first sub-micromolar, selective M<sub>5</sub> PAM

246th National Meeting (2013)

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Discovery of ML326: The first sub-micromolar, selective M5 PAM

Discovery of ML326: The first sub-micromolar, selective M₅ PAM