Structure Activity Relationship For Steroids At The Gabaa Receptor

Initial studies of the structural requirements for steroid interaction with the GABAa receptor emphasized active compounds to possess a 5a- or 5^-reduced pregnane (or androstane) skeleton with an a-hydroxyl at C3 of the steroid A ring and a keto group at either C20 of the pregnane steroid side chain or C17 of the androstane ring system (2,14,26,30,51,52). The compounds 3a,5a-THPROG, 3a,5|3-THPROG, 3a,5a-THDOC, and androsterone (3a-hydroxy-5a-androstan-17-one) are prototypical in this respect. Subsequent investigations, which have probed the steroid structure activity relationship (SAR) in greater detail, have led to considerable refinement and extension of this scheme. In particular, it is probably inappropriate to refer simplistically to a single SAR. Complications arise first from GABAa receptor heterogeneity, which may provide for binding sites at which steroids display differing affinities and/or efficacies (see Heterogeneity of Neurosteroid Binding Sites), and second, from the fact that the GABA-modulatory and GABA-mimetic activities of the steroids can be differentially influenced by the subunit composition of the receptor (see Role of 5 and e Subunits). The following summary of the SAR for steroid interaction with the GABAa receptor should thus be read with the caveat that it may not be universally applicable.

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