Steroid potentiation and inhibition of N-methyl-D-aspartate receptor- mediated intracellular Ca++ responses: Structure-activity studies

R. P. Irwin, S. Z. Lin, Michael A Rogawski, R. H. Purdy, S. M. Paul

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154 Scopus citations


Pregnenolone sulfate and 15 related steroids were investigated for their effects on N-methyl-D-aspartate (NMDA)-induced elevations in intracellular Ca++ ([Ca++](i)) in cultured rat hippocampal neurons by microspectrofluorimetry with the Ca++-sensitive indicator fura-2. Several pregn-5-ene steroids markedly potentiated NMDA-mediated [Ca++](i) responses. Pregnenolone sulfate and its 21-acetoxy derivative and pregnenolone hemisuccinate were the most active. At a concentration of 50 μM, each produced approximately 300% potentiation of 5 μM NMDA responses. In addition, several steroids were identified that inhibited NMDA-induced elevations in [Ca++](i), the most potent of which was 3α-hydroxy-5β- pregnan-20-one sulfate (IC50, 37 μM). Concentration-response curves for NMDA in the presence of active steroids revealed noncompetitive interaction(s) of these steroids with the NMDA receptor. Although the mechanism(s) responsible for either steroid-induced augmentation or inhibition of NMDA-receptor responses is unknown, these data suggest the presence of one or more steroid recognition sites with a high degree of structural specificity associated with NMDA receptors. These results further raise the possibility that pregn-5-ene 3-sulfates and pregnane 3-sulfates could be endogenous modulators of NMDA receptor-mediated synaptic events.

Original languageEnglish (US)
Pages (from-to)677-682
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - 1994
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology


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