ChemInform Abstract: 3α‐Hydroxy‐3β‐(phenylethynyl)‐5β‐pregnan‐20‐ones: Synthesis and Pharmacological Activity of Neuroactive Steroids with High Affinity for GABAA Receptors.

Abstract

1997 steroids steroids U 0300 17 -197 3α-Hydroxy-3β-(phenylethynyl)-5β-pregnan-20-ones: Synthesis and Pharmacological Activity of Neuroactive Steroids with High Affinity for GABAA Receptors.-The in vitro structure-activity relation of a series of title compounds is determined by their potency for inhibition of (35S)-tert-butylbicyclophosphorothionate in rat brain membranes. The product with the highest affinity for the neuroactive steroid site on GABAA receptors is (IIIa), while (IIIb) shows an attractive anticonvulsant activity. -(UPASANI, R. B.; YANG, K. C.; ACOSTA-BURRUEL, M.; KONKOY, C. S.; MCLELLAN, J. A.; WOODWARD, R. M.; LAN, N. C.; CARTER, R. B.; HAWKINSON, J.

Structure-Activity Relationships of Neuroactive Steroids Acting on the GABAA Receptor

“…In line with the above studies, Covey and coworkers prepared and evaluated a series of 13,24-cyclo-18,21-dinorcholanes containing a ketone or a conjugated ketone group at C-20, C-22, C-23 or C-24 (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) [28]. These ana- logues with conformationally constrained side chains were used to gain new information concerning the optimal location(s) for a hydrogen bond accepting group on the D-ring.…”

“…using [ 3 H]-t-butylbicycloorthobenzoate ([ 3 H]TBOB) to label a chloride ionophore associated binding site within the GABA A receptor complex are less common than those using [ 35 S]TBPS, although the use of this radiolabeled ligand appears to be more convenient due to the longer half-life of tritium compared to 35 S. Since both ligands are supposed to label the same populations of binding sites, studies using the two radioligands may well be compared [16]. Displacement of the specific binding of [ 3 H]-4´-ethynyl-4-n-propyl-bicycloorthobenzoate ([ 3 H]EBOB) follows an allosteric binding model that was first applied to glycine receptors which belong to the same superfamily of transmitter-gated ion channels as the GABA A receptor.…”

“…These results showed that 3 -substitution slowed metabolism of the 3-hydroxyl by blocking oxidation to the 3-ketone, resulting in orally bioavailable steroid modulators of the GABA A receptor. During the synthesis of the potent 3 -ethynyl-3 -hydroxy-5 -pregnan-20-one (110), the dimer 116 was isolated as a byproduct [35]. Although this steroid derivative had relatively low potency in the [ 35 S]TBPS assay, even this level of activity was surprising considering the bulk of the 3 -substituent.…”

“…Therefore, a further modification of the 3 -position was carried out by adding a spacer between the phenyl ring and the steroid nucleus to evaluate whether a bridging unit could provide enhanced potency. The spacers used were flexible or rigid chains of 1-3 carbon atoms [35].…”

Neurosteroids for the potential protection of humans against organophosphate toxicity

“…Structure–activity relationship studies at synaptic γGABA A receptors show that the C3α‐OH steroid structure is essential for the binding and the receptor‐enhancing function of neurosteroids . Apart from 5α‐H stereoselectivity, the C17‐ or C20‐ketone group is important for allosteric modulation . Neurosteroids bind to all GABA A receptors, but δ‐containing receptors at peri‐ and extrasynaptic sites exhibit preferential sensitivity .…”