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

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 R-max (I-max/I(max)5-HT) of 0.64 and 0.45 respectively It is about 10 fold less potent than 5-HT: EC50 = 16 and 27 mu M, and K-i for displacement of[H-3]granisetron binding= 0.8 and 1.8 mu M 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 (R-max = 0.15), low affinity (EC50= 113 mu M; K-i =4.8 mu M) partial agonist, while 5-chlorotryptamine has a similar affinity to 5-FT (EC(50=)8.1 mu M; K-i=2.7 mu M) but is a very weak partial agonist (R-max =0. 0037). These, and data from 5-methyltryptarnine and 5-methoxytryptamine, reveal the importance of size and electronegativity at this location for efficient channel opening. (C) 2007 Published by Elsevier B.V.