Bower KS et al. (2008), 5-Fluorotryptamine is a partial agonist at 5-HT...

XB-ART-37826

Eur J Pharmacol 2008 Feb 12;5803:291-7. doi: 10.1016/j.ejphar.2007.11.014.

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5-Fluorotryptamine is a partial agonist at 5-HT3 receptors, and reveals that size and electronegativity at the 5 position of tryptamine are critical for efficient receptor function.

Bower KS , Price KL , Sturdee LE , Dayrell M , Dougherty DA , Lummis SC .

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Antagonists, but not agonists, of the 5-HT3 receptor are useful therapeutic agents, and it is possible that partial agonists may also be potentially useful in the clinic. Here we show that 5-fluorotryptamine (5-FT) is a partial agonist at both 5-HT3A and 5-HT3AB receptors with an Rmax (Imax/Imax 5-HT) of 0.64 and 0.45 respectively. It is about 10 fold less potent than 5-HT: EC50=16 and 27 microM, and Ki for displacement of [3H]granisetron binding=0.8 and 1.8 microM for 5-HT3A and 5-HT3AB receptors respectively. We have also explored the potencies and efficacies of tryptamine and a range of 5-substituted tryptamine derivatives. At 5-HT3A receptors tryptamine is a weak (Rmax=0.15), low affinity (EC50=113 microM; Ki=4.8 microM) partial agonist, while 5-chlorotryptamine has a similar affinity to 5-FT (EC50=8.1 microM; Ki=2.7 microM) but is a very weak partial agonist (Rmax=0. 0037). These, and data from 5-methyltryptamine and 5-methoxytryptamine, reveal the importance of size and electronegativity at this location for efficient channel opening.

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Species referenced: Xenopus
Genes referenced: tbx2

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	Fig. 1. Structures of the 5-HT3 receptor agonists used in this study.
	Fig. 2. Properties of 5-HT3A and 5-HT3AB receptors expressed in Xenopus oocytes. Typical responses to maximal concentrations of 5-HT, mCPBG, 5-FT and tryptamine in (A) 5-HT3A and (B) 5-HT3AB receptors; (C) Concentration–response curves in 5-HT3A receptors; (D) Relative efficacies (Rmax) of agonists compared to 5-HT.
	Fig. 3. Alignment of 5-HT3A and 5-HT3B subunit sequences. Residues that have similar chemical properties are shown in grey. The binding loops that constitute the binding site are underlined.
	Fig. 4. 5-HT docked into a homology of the 5-HT3 receptor (Reeves et al., 2003). A. The extracellular domains of two subunits of the 5-HT3 receptor showing the location of the binding pocket (boxed) at their interface. B. Enlarged image of the binding site showing the proximity of the hydroxyl group of 5-HT to the hydrophilic residues Asn128, Glu129 Thr179, Thr181 and Glu236.