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Binding of O-Alkyl Derivatives of Serotonin at Human 5-HT1Dβ Receptors | Journal of Medicinal Chemistry
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    Binding of O-Alkyl Derivatives of Serotonin at Human 5-HT1Dβ Receptors
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    Department of Medicinal Chemistry, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298-0540, Allelix Biopharmaceutical, Mississauga, Ontario L4V 1V7, Canada, and Department of Pharmacology, Albany Medical College, Albany, New York 12208
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 1996, 39, 1, 314–322
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    https://doi.org/10.1021/jm950498t
    Published January 5, 1996
    Copyright © 1996 American Chemical Society
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    Abstract

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    In humans, 5-HT1D serotonin receptors represent terminal autoreceptors, and there is some evidence that 5-HT1D ligands may be useful in the treatment of migraine. The most widely used 5-HT1D agonist is sumatriptan; however, this agent reportedly displays little selectivity for 5-HT1D versus 5-HT1A receptors. To identify novel serotonergic agents with enhanced 5-HT1D versus 5-HT1A selectivity, we attempted to take advantage of possible differences in the regions of bulk tolerance associated with the 5-position of the 5-HT binding sites for these two populations of receptors. Examination of a series of 5-(alkyloxy)tryptamine derivatives demonstrated that compounds with unbranched alkyl groups of up to eight carbon atoms bind with high affinity at human 5-HT1Dβ receptors (Ki < 5 nM) but demonstrate less than 50-fold selectivity relative to 5-HT1A receptors. Alkyl groups longer than eight carbon atoms impart reduced affinity for 5-HT1A receptors whereas groups longer than nine carbon atoms lead to compounds with reduced affinity at 5-HT1Dβ receptors. 5-(Nonyloxy)tryptamine (10) represents a compound with optimal 5-HT1Dβ affinity (Ki = 1 nM) and selectivity (>300-fold). Branching of the alkyl chain, to 5-[(7,7-dimethylheptyl)oxy]tryptamine (15), results in an agent with somewhat lower affinity (5-HT1Dβ Ki = 2.3 nM) but with greater (i.e., 400-fold) 5-HT1D versus 5-HT1A selectivity. Replacement of the oxygen atom of 10 with a methylene group (i.e., 20), replacement of the O-proximate methylene with a carbonyl group (i.e., ester 26), or cyclization of the aminoethyl moiety to a carbazole (e.g., 34, 36) or β-carboline (i.e., 37), result in reduced affinity and/or selectivity. None of the compounds examined displayed significant selectivity for 5-HT1Dβ versus 5-HT1Dα sites; nevertheless, compounds 10 (recently shown to behave as a 5-HT1D agonist) and 15 represent the most 5-HT1D versus 5-HT1A selective agents reported to date.

    Copyright © 1996 American Chemical Society

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    †

     Virginia Commonwealth University.

    ‡

     Allelix Biopharmaceutical.

    §

     Albany Medical College.

    ✗

     Abstract published in Advance ACS Abstracts, December 15, 1995.

    Cited By

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 1996, 39, 1, 314–322
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm950498t
    Published January 5, 1996
    Copyright © 1996 American Chemical Society
    Request reuse permissions

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