Geometry and charge determine pharmacological effects of steroids on N-methyl-D-aspartate receptor-induced Ca2+ accumulation and cell death

Modulation of N-methyl-D-aspartate (NMDA) receptor function by a series of sulfated steroids and dicarboxylic acid ester analogs of pregnenolone sulfa te and pregnanolone sulfate was investigated in cultured hippocampal neuron s. The "bent" steroid ring structure associated with 5 beta-stereochemistry favors receptor inhibition, whereas the more planar ring structure of the pregn-5-enes and 5 alpha-pregnanes favors potentiation of NMDA-induced [Ca2 +] increases and neuronal cell death. The nature of the negatively charged group attached to the steroid C3 position is important for both the neuropr otection afforded by pregnane steroids and the exacerbation of NMDA-induced neuronal death by pregn-5-enes. Dicarboxylic acid hemiesters of various le ngths can substitute for the sulfate group of the positive modulator pregne nolone sulfate and the negative modulator pregnanolone sulfate. This result suggests that precise coordination with the oxygen atoms of the sulfate gr oup is not critical for modulation and that the steroid recognition sites c an accommodate bulky substituents at C3. The capacity of charged steroids t o enhance or protect against NMDA-induced death of hippocampal neurons is s trongly correlated with modulation of NMDA-induced Ca2+ accumulation, indic ating that direct enhancement or inhibition of NMDA receptor function is re sponsible for the proexcitotoxic or neuroprotective effects of these steroi ds.