PT - JOURNAL ARTICLE AU - Michael T. Klein AU - Małgorzata Dukat AU - Richard A. Glennon AU - Milt Teitler TI - Toward Selective Drug Development for the Human 5-Hydroxytryptamine 1E Receptor: A Comparison of 5-Hydroxytryptamine 1E and 1F Receptor Structure-Affinity Relationships AID - 10.1124/jpet.111.179606 DP - 2011 Jun 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 860--867 VI - 337 IP - 3 4099 - http://jpet.aspetjournals.org/content/337/3/860.short 4100 - http://jpet.aspetjournals.org/content/337/3/860.full SO - J Pharmacol Exp Ther2011 Jun 01; 337 AB - 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-HT1E receptors might be linked to memory. To test this hypothesis, behavioral experiments are needed. Because rats and mice lack a 5-HT1E receptor gene, knockout strategies cannot be used to elucidate this receptor's functions. Thus, selective pharmacological tools must be developed. The tryptamine-related agonist BRL54443 [5-hydroxy-3-(1-methylpiperidin-4-yl)-1H-indole] is one of the few agents that binds 5-HT1E receptors with high affinity and some selectively; unfortunately, it binds equally well to 5-HT1F receptors (Ki ≈ 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-HT1E receptors versus 5-HT1F receptors. Previously, we determined the receptor binding affinities of a large series of tryptamine analogs at the 5-HT1E receptor; we now examine the affinities of this same series of compounds at 5-HT1F receptors. The affinities of these compounds at 5-HT1E and 5-HT1F receptors were found to be highly correlated (r = 0.81). All high-affinity compounds were full agonists at both receptor populations. We identified 5-N-butyryloxy-N,N-dimethyltryptamine as a novel 5-HT1F receptor agonist with >60-fold selectivity versus 5-HT1E receptors. There is significant overlap between 5-HT1E and 5-HT1F receptor orthosteric binding properties; thus, identification of 5-HT1E-selective orthosteric ligands will be difficult. The insights generated from this study will inform future drug development and molecular modeling studies for both 5-HT1E and 5-HT1F receptors.