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-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.
Footnotes
This work was supported by the National Institutes of Health National Institute of Mental Health [Grant MH56650] (to M.T.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.179606.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- 5-HT
- 5-hydroxytryptamine
- h5-HT
- human 5-HT receptor
- DMT
- N,N-dimethyltryptamine
- BODMT
- 5-N-butyryloxy-DMT
- BRL54443
- 5-hydroxy-3-(1-methylpiperidin-4-yl)-1H-indole
- FSAC
- forskolin-stimulated adenylate cyclase
- GPCR
- G protein-coupled receptor
- LY334370
- 4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]-benzamide
- LY344864
- N-[(3R)-3-(dimethylamino)-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-4-fluorobenzamide
- LY349950
- 5-(4-flurorobenzamido)-2-methyl-N,N-dimethyltryptamine
- mACh
- muscarinic acetylcholine receptor
- SAR
- structure-activity relationship
- DMEM
- Dulbecco's modified Eagle's medium
- G418
- (2R,3S,4R,5R,6S)-5-amino-6-[(1R,2S,3S,4R,6S)-4,6-diamino-3-[(2R,3R,4R,5R)-3,5-dihydroxy-5-methyl-4-methylaminooxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-2-(1-hydroxyethyl)oxane-3,4-diol.
- Received January 25, 2011.
- Accepted March 17, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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