Binding of O-Alkyl Derivatives of Serotonin at Human 5-HT1Dβ Receptors

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 (K<INF>i</INF> &lt; 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 (<BO>10</BO>) represents a compound with optimal 5-HT1Dβ affinity (K<INF>i</INF> = 1 nM) and selectivity (>300-fold). Branching of the alkyl chain, to 5-[(7,7-dimethylheptyl)oxy]tryptamine (<BO>15</BO>), results in an agent with somewhat lower affinity (5-HT1Dβ K<INF>i</INF> = 2.3 nM) but with greater (i.e., 400-fold) 5-HT1D versus 5-HT1A selectivity. Replacement of the oxygen atom of <BO>10</BO> with a methylene group (i.e., <BO>20</BO>), replacement of the O-proximate methylene with a carbonyl group (i.e., ester <BO>26</BO>), or cyclization of the aminoethyl moiety to a carbazole (e.g., <BO>34</BO>, <BO>36</BO>) or β-carboline (i.e., <BO>37</BO>), result in reduced affinity and/or selectivity. None of the compounds examined displayed significant selectivity for 5-HT1Dβ versus 5-HT1Dα sites; nevertheless, compounds <BO>10</BO> (recently shown to behave as a 5-HT1D agonist) and <BO>15</BO> represent the most 5-HT1D versus 5-HT1A selective agents reported to date.