RT Journal Article SR Electronic T1 Substituted 3β-Phenylethynyl Derivatives of 3α-Hydroxy-5α-pregnan-20-one: Remarkably Potent Neuroactive Steroid Modulators of γ-Aminobutyric AcidA Receptors JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 198 OP 207 VO 287 IS 1 A1 Jon E. Hawkinson A1 Manuel Acosta-Burruel A1 Kevin C. Yang A1 Derk J. Hogenkamp A1 Jie-Sheng Chen A1 Nancy C. Lan A1 John A. Drewe A1 Edward R. Whittemore A1 Richard M. Woodward A1 Richard B. Carter A1 Ravindra B. Upasani YR 1998 UL http://jpet.aspetjournals.org/content/287/1/198.abstract AB Neuroactive steroids are positive allosteric modulators of γ-aminobutyric acidA (GABAA) receptor complexes. Synthetic modification generally does not increase neuroactive steroid potency beyond that of the naturally occurring progesterone metabolite, 3α-hydroxy-5α-pregnan-20-one (3α,5α-P). Recently, it has been shown that introduction of appropriately para-substituted phenylethynyl groups at the 3β-position of 5β steroids increases receptor potency. The present report presents the synthesis and pharmacological profile of an analogous series of 5α steroids. The most striking feature of this series is the further enhancement of in vitro andin vivo potency obtained. In particular, 3β-(p-acetylphenylethynyl)-3α-hydroxy-5α-pregnan-20-one (Co 152791) was 11-, 16- and 49-fold more potent than 3α,5α-P in modulating the binding of [35S]TBPS, [3H]flunitrazepam and [3H]muscimol, respectively, in rat brain membranes (Co 152791 IC50 or EC50 = 2–7.5 nM). Similarly, Co 152791 was 3- to 20-fold more potent than 3α,5α-P as an inhibitor of [35S]TBPS binding in human recombinant receptor combinations containing α1, α2, α3 or α5 and β2γ2L subunits (Co 152791 IC501.4–5.7 nM). Co 152791 displayed low efficacy and 3α,5α-P had low potency at α4/6β3γ2L GABAA receptor complexes. Interestingly, Co 152791 demonstrated remarkable potency as a potentiator of GABA-evoked currents in Xenopus oocytes expressing α1β2γ2L receptors (EC50 0.87 nM), being 184-fold more potent than 3α,5α-P. High in vitropotency was also reflected in enhanced in vivo activity in that Co 152791 exhibited exceptional anticonvulsant potency, protecting mice from pentylenetetrazol-induced seizures at a ∼5-fold lower dose than 3α,5α-P after i.p. administration (Co 152791 ED50 0.6 mg/kg). Moreover, Co 152791 was orally active (ED50 1.1 mg/kg) and exhibited a therapeutic index of 7 relative to rotorod impairment. The remarkable potency of Co 152791 as a positive allosteric modulator of GABAA receptors may be explained by its interaction with an auxiliary binding pocket in the neuroactive steroid binding site. In addition, modification at the 3β-position probably hinders metabolism of the 3α-hydroxy group contributing to the exceptional anticonvulsant potency of this compound relative to other neuroactive steroids. The American Society for Pharmacology and Experimental Therapeutics