Drug Design Targeting the Muscarinic Receptors and the Implications in Central Nervous System Disorders

  • Biomedicines. 2022 Feb 7;10(2):398. doi: 10.3390/biomedicines10020398.
Chad R Johnson  1 ,  Brian D Kangas  2 ,  Emily M Jutkiewicz  3 ,  Jack Bergman  2 ,  Andrew Coop  1
Affiliations
  • 1. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Pharmacy Hall North Room 623, 20 N. Pine St., Baltimore, MD 21202, USA.
  • 2. Behavioral Biology Program, McLean Hospital, Harvard Medical School, 115 Mill St., Belmont, MA 02478, USA.
  • 3. Department of Pharmacology, University of Michigan, 1150 W. Medical Center Dr., Ann Arbor, MI 48109, USA.
PMID: 35203607 DOI: 10.3390/biomedicines10020398
Abstract

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.

Keywords
Alzheimer’s disease; depression; drug design; major depressive disorder; muscarinic agonist; muscarinic antagonist; muscarinic receptors; positive allosteric modulator; schizophrenia.
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