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This Letter details our efforts to develop novel tricyclic muscarinic acetylcholine receptor subtype 4 (M 4 ) positive allosteric modulator (PAM) scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-5-chloro-4,6-dimethylthieno[2,3- b ]pyridine-2-carboxamide core, which led to the discovery of two novel tricyclic cores: an 8-chloro-9-methylpyrido[3',2':4,5]thieno[3,2- d ]pyrimidin-4-amine core and 8-chloro-7,9-dimethylpyrido[3',2':4,5]furo[3,2- d ]pyrimidin-4-amine core. Both tricyclic cores displayed low nanomolar potency against human M 4 and greatly reduced cytochrome P450 inhibition when compared with parent compound ML253 ., Competing Interests: The authors declare the following competing financial interest(s): R.A.C., S.R.B., J.L.E., M.F.L., C.W.L., P.J.C., T.M.B., D.W.E., and K.J.T. are inventors on applications for composition of matter patents that protect several series of M4 positive allosteric modulators., (© 2024 The Authors. Published by American Chemical Society.)

Herein, we report the chemical optimization of a new series of M 1 positive allosteric modulators (PAMs) based on a novel pyrrolo[2,3- b ]pyridine core, developed via scaffold hopping and iterative parallel synthesis. The vast majority of analogs in this series proved to display robust cholinergic seizure activity. However, by removal of the secondary hydroxyl group, VU6007477 resulted with good rat M 1 PAM potency (EC 50 = 230 nM, 93% ACh max), minimal M 1 agonist activity (agonist EC 50 > 10 μM), good CNS penetration (rat brain/plasma K p = 0.28, K p,uu = 0.32; mouse K p = 0.16, K p,uu = 0.18), and no cholinergic adverse events (AEs, e.g., seizures). This work demonstrates that within a chemical series prone to robust M 1 ago-PAM activity, SAR can result, which affords pure M 1 PAMs, devoid of cholinergic toxicity/seizure liability., Competing Interests: The authors declare the following competing financial interest(s): Hold IP on M1 PAMs.

Herein, we detail the optimization of the mGlu 3 NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu 3 NAM scaffold that engenders potent and selective mGlu 3 inhibition (mGlu 3 IC 50 = 245 nM, mGlu 2 IC 50 > 30 μM) with excellent central nervous system penetration (rat brain/plasma K p = 1.2, K p,uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and in vivo efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).