A neuroactive steroid with a therapeutically interesting constellation of actions at GABAA 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, 3ß-hydroxy neurosteroid analogue that inhibits NMDAR function but also potentiates GABAAR function, thereby exhibiting unusual but potentially clinically desirable effects. Although the compound also exhibited features of other sulfated steroids, namely activation-dependent inhibition of GABAAR function, net potentiation dominated under physiological conditions. Potentiation of GABAAR function was distinct from the mechanism governing potentiation by anesthetic neurosteroids. Inhibition of NMDAR function showed weaker channel activation dependence than pregnanolone sulfate (3α5ßPS). 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.