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Partial Agonism by 3alpha,21-dihydroxy-5beta-pregnan-20-one at the Gamma-Aminobutyric acidA Receptor Neurosteroid Site

Partial Agonism by 3alpha,21-dihydroxy-5beta-pregnan-20-one at the Gamma-Aminobutyric acidA Receptor Neurosteroid Site

B G Xue, E R Whittemore, C H Park, R M Woodward, N C Lan, K W Gee

J Pharmacol Exp Ther. 1997 Jun;281(3):1095-101.

PMID: 9190841

Abstract:

3alpha,21-Dihydroxy-5alpha-pregnan-20-one (5alpha-THDOC) and 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-P) have full efficacy as allosteric modulators of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding to sites on the gamma-aminobutyric acid (GABA) type A receptor complex (GRC). Relative to 3alpha,5alpha-P and 5alpha-THDOC, 3alpha,21-dihydroxy-5beta-pregnan-20-one (5beta-THDOC) has limited efficacy as an allosteric modulator of [35S]TBPS binding. Interactions between 3alpha,5alpha-P, 5alpha-THDOC and 5beta-THDOC were examined to determine whether these neuroactive steroids share a common site for modulation of the GRC. The concentration-response curves for both 3alpha,5alpha-P and 5alpha-THDOC modulation of [35S]TBPS binding to brain and recombinantly derived GRCs are shifted rightward in the presence of various concentrations of 5beta-THDOC. Similarly, 5beta-THDOC modulates GABA-evoked Cl- currents with low efficacy and inhibits the potentiation of GABA-evoked Cl- currents by 3alpha,5alpha-P. Furthermore, behavioral studies reveal that 5beta-THDOC antagonizes 3alpha,5alpha-P-induced loss of the righting reflex in mice at a dose that has no effect alone. These results represent the first demonstration of antagonist-like actions of a neuroactive steroid on the GRCs at levels ranging from the receptor to animal behavior and suggest the existence of partial agonist neurosteroids.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP567022	3α,21-Dihydroxy-5α-pregnan-20-one		567-02-2	Price

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