Neurosteroid Analogues. 9. Conformationally Constrained Pregnanes: Structure-Activity Studies of 13,24-Cyclo-18,21-dinorcholane Analogues of the GABA Modulatory and Anesthetic Steroids (3α,5α)- and (3α,5β)-3-Hydroxypregnan-20-one

Xin Jiang, Brad D. Manion, Ann Benz, Nigam P. Rath, Alex S. Evers, Charles F. Zorumski, Steven Mennerick, Douglas F. Covey

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

The hydrogen-bond-acceptor properties of the carbonyl moiety in the 17β-acetyl group on the D-ring of the anesthetic steroids (3α,5α)- and (3α5α)-3-hydroxypregan-20-one form an important part of the anesthetic steroid pharmacophore. 13,24-Cyclo-18,21-dinorcholanes containing a ketone or conjugated ketone group at C-20, C-22, C-23, or C-24 were prepared as conformationally constrained analogues of these anesthetic steroids and were used to probe for alternate locations for the D-ring hydrogen-bond-accepting carbonyl group. The analogues were evaluated (1) in [35S]-tert-butylbicyclophosphorothionate binding experiments, (2) in electrophysiological experiments using rat α1β2γ2L GABAA receptors expressed in Xenopus laevis oocytes, and (3) as tadpole anesthetics. In the binding assay, the relative order of potencies for the analogues in the 5α- and 5β-series is identical. For the ketones, the order is 24-one ≥ 23-one > 20-one > 22-one. Likewise, for the enones, the order is Δ22-24-one > Δ20(22)-23-one > Δ22-20-one > Δ23-22-one. Similar relative orders of potencies are also found in the other two bioassays. The activities of the 24-one and Δ22-24-one compounds were expected to be very low, because the carbonyl group in these compounds is located over the steroid C-ring and oriented toward C-8. Instead, these compounds have the highest activities in their respective series, with the Δ 22-24-one compounds having activities comparable to those of the reference anesthetic steroids. The electrophysiology results obtained with the 24-oxo-cyclosteroids suggest that rat α1β 2γ2L GABAA receptors contain more than one donor for the hydrogen-bond-acceptor group of anesthetic steroids. The family of cyclosteroids should be useful for future structure-activity relationship studies of steroid modulation of other GABAA receptor subtypes.

Original languageEnglish
Pages (from-to)5334-5348
Number of pages15
JournalJournal of Medicinal Chemistry
Volume46
Issue number25
DOIs
StatePublished - Dec 4 2003

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