A neuroactive steroid with a therapeutically interesting constellation of actions at GABAA and NMDA receptors. (1st February 2021)

• Record Type: Journal Article
• Authors: Ziolkowski, Luke; Mordukhovich, Isaac; Chen, Daniel M.; Chisari, Mariangela; Shu, Hong-Jin; Lambert, Peter M.; Qian, Mingxing; Zorumski, Charles F.; Covey, Douglas F.; Mennerick, Steven
• Is Part Of: Neuropharmacology. Volume 183(2021)
• Publication Date: 2021-02-01
• Subjects: GABA -- Glutamate -- NMDA -- Antidepressant -- Neurosteroid; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2020.108358
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Neuroactive steroids are an ascendant class of treatment for neuropsychiatric illness. Effects on ligand-gated neurotransmitter receptors appear to be a major mechanism of action. Here we describe a neuroactive steroid with a unique constellation of receptor actions. MQ-221 is a sulfated, 3β-hydroxy neurosteroid analogue that inhibits NMDAR function but also potentiates GABAA R function, thereby exhibiting unusual but potentially clinically desirable effects. Although the compound also exhibited features of other sulfated steroids, namely activation-dependent inhibition of GABAA R function, net potentiation dominated under physiological conditions. Potentiation of GABAA R function was distinct from the mechanism governing potentiation by anesthetic neurosteroids. Inhibition of NMDAR function showed weaker channel activation dependence than pregnanolone sulfate (3α5βPS). MQ-221 was unique among four stereoisomers explored in the pattern of effects at GABAA and NMDARs. Taken together, MQ-221 may represent a new class of compound with unique psychoactive effects and beneficial prospects for treating neuropsychiatric disorders. Highlights: MQ-221 is a first-in-class neuroactive steroid. MQ-221 potentiates GABAA receptors through a mechanism unlike neurosteroids. MQ-221 inhibits NMDA receptors, preferring GluN2B-containing receptors.