A neuroactive steroid with a therapeutically interesting constellation of actions at GABA A and NMDA receptors

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, 3 beta-hydroxy neurosteroid analogue that inhibits NMDAR function but also potentiates GABA(A)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 GABA(A)R function, net potentiation dominated under physiological conditions. Potentiation of GABA(A)R function was distinct from the mechanism governing potentiation by anesthetic neurosteroids. Inhibition of NMDAR function showed weaker channel activation dependence than pregnanolone sulfate (3 alpha 5 beta PS). MQ-221 was unique among four stereoisomers explored in the pattern of effects at GABA(A) and NMDARs. Taken together, MQ-221 may represent a new class of compound with unique psychoactive effects and beneficial prospects for treating neuropsychiatric disorders.

Automated summary

Neuroactive steroids are emerging as a new class of drugs for treating neuropsychiatric disorders, with effects on ligand-gated neurotransmitter receptors being a major mechanism of action. MQ-221, a sulfated, 3 beta-hydroxy neurosteroid analogue, inhibits NMDAR function while potentiating GABA(A)R function, showing potentially unique and clinically desirable effects. It may represent a new class of compound with unique psychoactive effects and beneficial prospects for treating neuropsychiatric disorders.