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Synthesis and in Vitro Activity of 3β-Substituted-3α-hydroxypregnan-20-ones:  Allosteric Modulators of the GABAA Receptor

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    Synthesis and in Vitro Activity of 3β-Substituted-3α-hydroxypregnan-20-ones:  Allosteric Modulators of the GABAA Receptor†
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    CoCensys, Inc., 213 Technology Drive, Irvine, California 92618, Department of Radiology, School of Medicine, and Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90033, and Department of Pharmacology, College of Medicine, University of California, Irvine, California 92717
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 1997, 40, 1, 61–72
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    https://doi.org/10.1021/jm960021x
    Published January 3, 1997
    Copyright © 1997 American Chemical Society
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    Abstract

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    Two naturally occurring metabolites of progesterone, 3α-hydroxy-5α- and 5β-pregnan-20-one (1 and 2), are potent allosteric modulators of the GABAA receptor. Their therapeutic potential as anxiolytics, anticonvulsants, and sedative/hypnotics is limited by rapid metabolism. To avoid these shortcomings, a series of 3β-substituted derivatives of 1 and 2 was prepared. Small lipophilic groups generally maintain potency in both the 5α- and 5β-series as determined by inhibition of [35S]TBPS binding. In the 5α-series, 3β-ethyl, -propyl, -trifluoromethyl and -(benzyloxy)methyl, as well as substituents of the form 3β-XCH2, where X is Cl, Br, or I or contains unsaturation, show limited efficacy in inhibiting [35S]TBPS binding. In the 5β-series, the unsubstituted parent 2 is a two-component inhibitor, whereas all of the 3β-substituted derivatives of 2 inhibit TBPS via a single class of binding sites. In addition, all of the 3-substituted 5β-sterols tested are full inhibitors of [35S]TBPS binding. Electrophysiological measurements using α1β2γ2L receptors expressed in oocytes show that 3β-methyl- and 3β-(azidomethyl)-3α-hydroxy-5α-pregnan-20-one (6 and 22, respectively) are potent full efficacy modulators and that 3α-hydroxy-3β-(trifluoromethyl)-5α-pregnan-20-one (24) is a low-efficacy modulator, confirming the results obtained from [35S]TBPS binding. These results indicate that modification of the 3β-position in 1 and 2 maintains activity at the neuroactive steroid site on the GABAA receptor. In animal studies, compound 6 (CCD 1042) is an orally active anticonvulsant, while the naturally occurring progesterone metabolites 1 and 2 are inactive when administered orally, suggesting that 3β-substitution slows metabolism of the 3-hydroxyl, resulting in orally bioavailable steroid modulators of the GABAA receptor.

    Copyright © 1997 American Chemical Society

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    †

     Presented in part at the 209th National Meeting of the American Chemical Society, Anaheim, CA, April 2−6, 1995.

    *

     Author for correspondence.

    ‡

     CoCensys, Inc.

    §

     Department of Radiology.

    ∇

     University of California.

    ‖

     Department of Pharmaceutical Sciences.

    ✗

     Abstract published in Advance ACS Abstracts, December 15, 1996.

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    Crystal structure data for 6 (10 pages); tables of observed and calculated structure factors (14 pages). Ordering information is given on any current masthead page.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 1997, 40, 1, 61–72
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm960021x
    Published January 3, 1997
    Copyright © 1997 American Chemical Society
    Request reuse permissions

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