title: 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-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.
authors: California Institute of Technology, Pasadena, California, USA.
authors: Kiowa S
authors: KS
authors: Bower
authors: Kerry L
authors: KL
authors: Price
authors: Laura E C
authors: LE
authors: Sturdee
authors: Mariza
authors: M
authors: Dayrell
authors: Dennis A
authors: DA
authors: Dougherty
authors: Sarah C R
authors: SC
authors: Lummis
mesh_terms: D008735:5-Methoxytryptamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D004594:Electrophysiology / Q000379:methods; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D017829:Granisetron / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D011955:Receptors, Drug / Q000819:agonists / Q000235:genetics / Q000502:physiology; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D058827:Serotonin 5-HT3 Receptor Agonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D014363:Tryptamines / Q000737:chemistry / Q000494:pharmacology*; D014981:Xenopus
chemical_list: D008735:5-Methoxytryptamine; D001643:Bridged Bicyclo Compounds; D005998:Glycine; D017829:Granisetron; D011955:Receptors, Drug; D044406:Receptors, Serotonin, 5-HT3; D058827:Serotonin 5-HT3 Receptor Agonists; D012702:Serotonin Antagonists; D014363:Tryptamines; C529169:5-chlorotryptamine; C100726:UPF 596; C027552:5-methyltryptamine; C030820:tryptamine; C034536:5-fluorotryptamine