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Abstract

The 5-hydroxytryptamine (5-HT) 1E receptor is highly expressed in the human frontal cortex and hippocampus, and this distribution suggests the function of 5-HT_1E receptors might be linked to memory. To test this hypothesis, behavioral experiments are needed. Because rats and mice lack a 5-HT_1E receptor gene, knockout strategies cannot be used to elucidate this receptor9s functions. Thus, selective pharmacological tools must be developed. The tryptamine-related agonist BRL54443 [5-hydroxy-3-(1-methylpiperidin-4-yl)-1<i>H</i>-indole] is one of the few agents that binds 5-HT_1E receptors with high affinity and some selectively; unfortunately, it binds equally well to 5-HT_1F receptors (<i>K</i>_i ≈ 1 nM). The differences between tryptamine binding requirements of these two receptor populations have never been extensively explored; this must be done to guide the design of analogs with greater selectivity for 5-HT_1E receptors versus 5-HT_1F receptors. Previously, we determined the receptor binding affinities of a large series of tryptamine analogs at the 5-HT_1E receptor; we now examine the affinities of this same series of compounds at 5-HT_1F receptors. The affinities of these compounds at 5-HT_1E and 5-HT_1F receptors were found to be highly correlated (<i>r</i> = 0.81). All high-affinity compounds were full agonists at both receptor populations. We identified 5-<i>N</i>-butyryloxy-<i>N</i>,<i>N</i>-dimethyltryptamine as a novel 5-HT_1F receptor agonist with &gt;60-fold selectivity versus 5-HT_1E receptors. There is significant overlap between 5-HT_1E and 5-HT_1F receptor orthosteric binding properties; thus, identification of 5-HT_1E-selective orthosteric ligands will be difficult. The insights generated from this study will inform future drug development and molecular modeling studies for both 5-HT_1E and 5-HT_1F receptors.

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