M1/M4 receptors as potential therapeutic treatments for schizophrenia: A comprehensive study.

Muscarinic acetylcholine receptors (mAChRs) play a significant role in the pathophysiology of schizophrenia. Although activating mAChRs holds potential in addressing the full range of schizophrenia symptoms, clinical application of many non-selective mAChR agonists in cognitive deficits, positive and negative symptoms is hindered by peripheral side effects (gastrointestinal disturbances and cardiovascular effects) and dosage restrictions. Ligands binding to the allosteric sites of mAChRs, particularly the M1 and M4 subtypes, demonstrate activity in improving cognitive function and amelioration of positive and negative symptoms associated with schizophrenia, enhancing our understanding of schizophrenia. The article aims to critically examine current design concepts and clinical advancements in synthesizing and designing small molecules targeting M1/M4, providing theoretical insights and empirical support for future research in this field.

Discovery of (2S)-N-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(6-(4-cyanophenyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-hydroxy-2-methylpropanamide as a Highly Potent and Selective Topical Androgen Receptor Antagonist for Androgenetic Alopecia Treatment.

Androgenetic alopecia (AGA) is the most prevalent form of progressive hair loss disorder in both men and women, significantly impacting their appearance and overall quality of life. Overactivation of the AR signaling pathway in dermal papilla cells (DPCs) plays a crucial role in the development and progression of AGA. Considering the severe systemic side effects associated with oral AR antagonists, the idea of developing of topical AR antagonists with rapid metabolic deactivation properties emerged as a promising approach. Herein, through systematic structural optimization, we successfully identified compound 30a as a potent and selective AR antagonist with favorable pharmacokinetic properties, resulting in high skin exposure and low plasma exposure following topical administration. Importantly, in both hair-growth and AGA mouse models, compound 30a showed potent hair-growth-promoting effects without any noticeable toxicity. These findings suggest that compound 30a holds significant potential as a topical AR antagonist for treating AGA patients.