3 alpha-Hydroxy-3 beta-(phenylethynyl)-5 beta-pregnan-20-ones: synthesis and pharmacological activity of neuroactive steroids with high affinity for GABAA receptors.
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.
Upasani
R B
RB
CoCensys, Inc., Irvine, California 92618, USA.
Yang
K C
KC
Acosta-Burruel
M
M
Konkoy
C S
CS
McLellan
J A
JA
Woodward
R M
RM
Lan
N C
NC
Carter
R B
RB
Hawkinson
J E
JE
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
D000927:Anticonvulsants; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018757:GABA Modulators; D011963:Receptors, GABA-A; C037476:tert-butylbicyclophosphorothionate; D011280:Pregnanolone