期刊
BIOCHEMICAL PHARMACOLOGY
卷 200, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2022.115028
关键词
5-HT2A; GPCR; Antipsychotic; Antagonist; Selectivity
资金
- National Institute on Drug Abuse (NIDA) [R01DA047130, R01DA030989]
- National Institute of Neurological Disorders and Stroke (NINDS) [R15 NS118352-01]
- U.S. Department of Defense [CDMRP W81XWH-17-1-0322]
- CDMRP [W81XWH-17-1-0329]
- Northeastern University David Bear Scholar Fund
- Northeastern University's Research Computing team
This review discusses the importance of blockade and activation of the serotonin 5-HT2A G protein-coupled receptor (5-HT2AR) in the treatment of psychiatric disorders, and the limitations and strengths of currently available selective 5-HT2AR antagonists.
Blockade of the serotonin 5-HT2A G protein-coupled receptor (5-HT2AR) is a fundamental pharmacological characteristic of numerous antipsychotic medications, which are FDA-approved to treat schizophrenia, bipolar disorder, and as adjunctive therapies in major depressive disorder. Meanwhile, activation of the 5-HT2AR by serotonergic psychedelics may be useful in treating neuropsychiatric indications, including major depressive and substance use disorders. Serotonergic psychedelics and other 5-HT2AR agonists, however, often bind other receptors, and standard 5-HT2AR antagonists lack sufficient selectivity to make well-founded mechanistic conclusions about the 5-HT2AR-dependent effects of these compounds and the general neurobiological function of 5HT(2A)Rs. This review discusses the limitations and strengths of currently available selective 5-HT2AR antagonists, the molecular determinants of antagonist selectivity at 5-HT(2A)Rs, and the utility of molecular pharmacology and computational methods in guiding the discovery of novel unambiguously selective 5-HT2AR antagonists.
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