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

Abstract

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-HT_(3A) and 5-HT_(3AB) 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 μM, and K_i for displacement of [³H]granisetron binding = 0.8 and 1.8 μM for 5-HT_(3A) and 5-HT_(3AB) receptors respectively. We have also explored the potencies and efficacies of tryptamine and a range of 5-substituted tryptamine derivatives. At 5-HT_(3A) receptors tryptamine is a weak (R_(max) = 0.15), low affinity (EC₅₀ = 113 μM; K_i = 4.8 μM) partial agonist, while 5-chlorotryptamine has a similar affinity to 5-FT (EC₅₀ = 8.1 μM; K_i = 2.7 μM) but is a very weak partial agonist (R_(max) = 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.