title: 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) ≈ 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 = 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-HT(1F) receptor agonist with >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.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Klein
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Dukat
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
authors.forename: Milt
authors.initials: M
authors.lastname: Teitler
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D016466:CHO Cells; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D010293:Pargyline / Q000494:pharmacology; D011485:Protein Binding; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000031:analogs & derivatives; D017366:Serotonin Receptor Agonists / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014363:Tryptamines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000096642:Receptor, Serotonin, 5-HT1F
chemical_list: D000959:Antihypertensive Agents; D005576:Colforsin; D010293:Pargyline; D011985:Receptors, Serotonin; D012701:Serotonin; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; D000096642:Receptor, Serotonin, 5-HT1F; C076396:serotonin 1E receptor