title: Neuroactive steroid modulation of [3H]muscimol binding to the GABAA receptor complex in rat cortex.
abstract: Epalons are a subclass of neuroactive steroids which are positive allosteric modulators of the GABAA receptor acting via a unique site on the receptor complex. Enhancement of [3H]muscimol binding to the GABA recognition site was observed to be either full (> 150%) or limited (110-135%) and specific for epalons. Both one and two component modulation was observed. Saturation studies performed in the presence of 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) showed that 3 alpha, 5 alpha-P increased the density of high affinity [3H]muscimol sites and doubled the affinity of low affinity sites. 3 alpha,5 alpha-P had no effect on the affinity of the high affinity site or the density of the low affinity site. These data indicate that: (1) epalons are potent, stereoselective enhancers of [3H]muscimol binding; (2) epalons display varying levels of efficacy and some exhibit two-component enhancement; and (3) 3 alpha,5 alpha-P enhancement of [3H]muscimol binding results from both an increased density of high affinity sites and an increased affinity for low affinity sites.
authors.affiliation: Department of Biochemical Pharmacology, CoCensys, Inc., Irvine, CA 92718, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Goodnough
authors.forename: J E
authors.initials: JE
authors.lastname: Hawkinson
mesh_terms: D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011280:Pregnanolone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013256:Steroids / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000777:Anesthetics; D011963:Receptors, GABA-A; D013256:Steroids; D011280:Pregnanolone