Geometry and charge determine pharmacological effects of steroids on N-methyl-D-aspartate receptor-induced Ca(2+) 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 sulfate and pregnanolone sulfate was investigated in cultured hippocampal neurons. The "bent" steroid ring structure associated with 5beta-stereochemistry favors receptor inhibition, whereas the more planar ring structure of the pregn-5-enes and 5alpha-pregnanes favors potentiation of NMDA-induced [Ca(2+)] increases and neuronal cell death. The nature of the negatively charged group attached to the steroid C3 position is important for both the neuroprotection afforded by pregnane steroids and the exacerbation of NMDA-induced neuronal death by pregn-5-enes. Dicarboxylic acid hemiesters of various lengths can substitute for the sulfate group of the positive modulator pregnenolone sulfate and the negative modulator pregnanolone sulfate. This result suggests that precise coordination with the oxygen atoms of the sulfate group is not critical for modulation and that the steroid recognition sites can accommodate bulky substituents at C3. The capacity of charged steroids to enhance or protect against NMDA-induced death of hippocampal neurons is strongly correlated with modulation of NMDA-induced Ca(2+) accumulation, indicating that direct enhancement or inhibition of NMDA receptor function is responsible for the proexcitotoxic or neuroprotective effects of these steroids.