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

摘要

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 / Imax5-HT) of 0.64 and 0.45 respectively. It is about 10 fold less potent than 5-HT: EC50 = 16 and 27 μM, and Ki for displacement of [³H]granisetron binding = 0.8 and 1.8 μM 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 μM; Ki = 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.