title: 3 alpha-Hydroxy-3 beta-(phenylethynyl)-5 beta-pregnan-20-ones: synthesis and pharmacological activity of neuroactive steroids with high affinity for GABAA receptors.
abstract: Neuroactive steroids that allosterically modulate GABAA receptors have potential uses as anticonvulsants, anxiolytics, and sedative-hypnotic agents. Recently, a series of pregnanes substituted with simple alkyl groups at the 3 beta-position were synthesized and found to be active in vitro. The present report describes the synthesis of a series of substituted 3 alpha-hydroxy-3 beta-(phenylethynyl)pregnan-20-ones and their in vitro structure-activity relationship determined by their potency for inhibition of [35S]TBPS binding in rat brain membranes. Appropriate substitution of the phenyl group results in ligands with particularly high affinity for the neuroactive steroid site on GABAA receptors (e.g., 4-acetyl 28, IC50 10 nM). The potency of selected steroids was confirmed electrophysiologically in oocytes expressing cloned human GABAA alpha 1 beta 2 gamma 2L receptors (e.g., compound 28, EC50 6.6 nM). Consistent with their in vitro activity, some of the 3 beta-(phenylethynyl)-substituted steroids displayed anticonvulsant activity in the pentylenetetrazol (PTZ) and maximal electroshock (MES) tests following ip administration in mice. Notably, the 3 beta-[(4-acetylphenyl)ethynyl]-19-nor derivative 36 demonstrated an attractive anticonvulsant profile (PTZ and MES ED50 values of 2.8 and 9.2 mg/kg, respectively). A new pharmacophore for the neuroactive steroid site of GABAA receptors is proposed based upon the high affinity of certain substituted 3 beta-(phenylethynyl) steroids.
authors.affiliation: CoCensys, Inc., Irvine, California 92618, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Upasani
authors.forename: K C
authors.initials: KC
authors.lastname: Yang
authors.forename: M
authors.initials: M
authors.lastname: Acosta-Burruel
authors.forename: C S
authors.initials: CS
authors.lastname: Konkoy
authors.forename: J A
authors.initials: JA
authors.lastname: McLellan
authors.forename: R M
authors.initials: RM
authors.lastname: Woodward
authors.forename: N C
authors.initials: NC
authors.lastname: Lan
authors.forename: R B
authors.initials: RB
authors.lastname: Carter
authors.forename: J E
authors.initials: JE
authors.lastname: Hawkinson
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D004594:Electrophysiology; D004597:Electroshock; D005260:Female; D018757:GABA Modulators / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D051379:Mice; D009865:Oocytes / Q000378:metabolism; D011280:Pregnanolone / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014981:Xenopus
chemical_list: D000927:Anticonvulsants; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018757:GABA Modulators; D011963:Receptors, GABA-A; C037476:tert-butylbicyclophosphorothionate; D011280:Pregnanolone