HETEROTROPIC COOPERATIVITY BETWEEN PUTATIVE RECOGNITION SITES FOR PROGESTERONE METABOLITES AND THE ATYPICAL BENZODIAZEPINE RO-5-4864

Abstract: The binding of the cage convulsant t‐butylbicyclo phosphorothionate (TBPS) and 36CI‐ uptake by synaptoneurosomes were used to test the ability of progesterone metabolites to modulate allosterically the Ro 5–4864 (4′‐chlorodiazepam) binding site that is functionally coupled to the γ‐aminobutyric acid (GABA)/benzodiazepine receptor complex (GBRC) in rat brain. Dose‐dependent enhancement of [35S]TBPS binding by Ro 5–4864 occurs in rat cerebral cortex in the presence of the progesterone metabolites 5αpregnan‐3α‐ol‐20‐one (3α‐OH‐DHP) and 5α‐pregnan‐3α, 20α‐diol(pregnanediol). The pregnanediol effect is completely GABA dependent, whereas that of 3α‐OH‐DHP is not. Conversely, Ro 5–4864 opposed the action of 3α‐OH‐DHP by increasing the IC50 for 3α‐OH‐DHP inhibition of [35S]TBPS binding. In cortical snaptoneurosomes, Ro 5–4864 antag onized both 3α‐OH‐DHP and pregnanediol enhancement of GABA‐stimulated 36CI‐ uptake. In both binding and functional studies, pregnanediol showed limited efficacy relative to 3α‐OH‐DHP, as previously reported. These findings provide the initial evidence that the GBRC‐linked Ro 5–4864 binding site is allosterically coupled to the putative progesterone metabolite recognition site and confirm the GABA mimetic properties of 3α‐OH‐DHP and pregnanediol. Copyright © 1990, Wiley Blackwell. All rights reserved