Toward Selective Drug Development for the Human 5-Hydroxytryptamine 1E Receptor: A Comparison of 5-Hydroxytryptamine 1E and 1F Receptor Structure-Affinity Relationships

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 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-HT 1E receptors with high affinity and some selectively; unfortunately, it binds equally well to 5-HT 1F receptors (K i Ϸ 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 (r ϭ 0.81). All high-affinity compounds were full agonists at both receptor populations. We identified 5-Nbutyryloxy-N,N-dimethyltryptamine as a novel 5-HT 1F receptor agonist with Ͼ60-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.

Forskolin-free cAMP assay for Gi-coupled receptors

“…We bought some of the compounds in another chemical form to confirm this hypothesis. For instance, compound 3E8 in the library, BRL 54443, a 5-hydroxytryptamine receptor 5-HT 1e & 5-HT 1F agonist [32], showed no activity alone in our assay (Fig. 6B) whereas maleic acid confirmed its activity and showed an EC 50 = 93.8 AE 1.3 mM and E max = 32.6 AE 3% when assayed in the presence of FSK.…”

5-HT Receptors and the Development of New Antidepressants

“…On the other hand, a postmortem study of untreated suicidal victims with a confirmed history of depression showed a much higher density of 5-HT 1D receptors in the globus pallidus [138]. The observed high expression of the 5-HT 1E receptor in the frontal cortex and hippocampus may indicate the relationship between 5-HT 1E receptors and cognitive functions and memory [20,139].…”

Distribution of 5‐ht1E receptors in the mammalian brain and cerebral vasculature: an immunohistochemical and pharmacological study

“…The 5‐ht 1E receptor has also never been shown to be functionally linked to a second messenger system in animal tissue; 5‐ht 1E receptors have only been shown to couple to G i/o signalling pathways in recombinant cell lines (Adham et al ., 1994; Klein et al ., 2011). BRL54443 is the only drug known to be partly selective for the 5‐ht 1E receptor; it is also equipotent at 5‐HT 1F receptors (Brown et al ., 1998).…”