Johnson Chad R, Kangas Brian D, Jutkiewicz Emily M, Bergman Jack, Coop Andrew
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Pharmacy Hall North Room 623, 20 N. Pine St., Baltimore, MD 21202, USA.
Behavioral Biology Program, McLean Hospital, Harvard Medical School, 115 Mill St., Belmont, MA 02478, USA.
Biomedicines. 2022 Feb 7;10(2):398. doi: 10.3390/biomedicines10020398.
There is substantial evidence that cholinergic system function impairment plays a significant role in many central nervous system (CNS) disorders. During the past three decades, muscarinic receptors (mAChRs) have been implicated in various pathologies and have been prominent targets of drug-design efforts. However, due to the high sequence homology of the orthosteric binding site, many drug candidates resulted in limited clinical success. Although several advances in treating peripheral pathologies have been achieved, targeting CNS pathologies remains challenging for researchers. Nevertheless, significant progress has been made in recent years to develop functionally selective orthosteric and allosteric ligands targeting the mAChRs with limited side effect profiles. This review highlights past efforts and focuses on recent advances in drug design targeting these receptors for Alzheimer's disease (AD), schizophrenia (SZ), and depression.
有大量证据表明，胆碱能系统功能障碍在许多中枢神经系统（CNS）疾病中起重要作用。在过去三十年中，毒蕈碱受体（mAChRs）与各种病理状况有关，并且一直是药物设计努力的主要靶点。然而，由于正构结合位点的高序列同源性，许多候选药物在临床上取得的成功有限。尽管在治疗外周疾病方面已经取得了一些进展，但针对中枢神经系统疾病仍然是研究人员面临的挑战。尽管如此，近年来在开发针对mAChRs的功能选择性正构和变构配体方面取得了重大进展，这些配体的副作用有限。本综述重点介绍了过去的努力，并关注针对这些受体治疗阿尔茨海默病（AD）、精神分裂症（SZ）和抑郁症的药物设计的最新进展。
