F 11356, a novel 5-hydroxytryptamine (5-HT) derivative with potent, selective, and unique high intrinsic activity at 5-HT(1B/1D) receptors in models relevant to migraine

Gareth W. John, Petrus J. Pauwels, Michel Perez, Serge Halazy, Bruno Le Grand, Wan Verscheure, Jean Pierre Valentin, Christiane Palmier, Thierry Wurch, Philippe Chopin, Marc Marien, Mark S. Kleven, Wouter Koek, Marie Bernadette Assie, Elisabeth Carilla-Durand, Jean Pierre Tarayre, Francis C. Colpaert

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31 Scopus citations

Abstract

F 11356 (4-[4-[2-(2-aminoethyl)-1H-indol-5-yloxyl]acetyl]piperazinyl-1- yl]benzonitrile) was designed to take advantage of the superior potency and efficacy characteristics of 5-hydroxytryptamine (5-HT) compared with tryptamine at 5-HT(1B/1D) receptors. F 11356 has subnanomolar affinity for cloned human and nonhuman 5-HT(1B) and 5-HT(1D) receptors, and its affinity for 5-HT(1A) and other 5-HT receptors, including the 5-ht(1F) subtype, is 50- fold lower and micromolar, respectively. In C6 cells expressing human 5- HT(1B) or human 5-HT(1D) receptors, F 11356 was the most potent compound in inhibiting forskolin-induced cyclic AMP formation (pD2 = 8.9 and 9.6), and in contrast to tryptamine and derivatives, it produced maximal enhancement of [35S]guanosine-5'-O-(3-thio)triphosphate-specific binding equivalent to 5- HT. F 11356 was equipotent to 5-HT (pD2 = 7.1 versus 7.2) and more potent than tryptamine derivatives in contracting rabbit isolated saphenous vein. In isolated guinea pig trigeminal ganglion neurons, F 11356 was more potent (pD2 = 7.3 versus 6.7) and induced greater increases in outward hyperpolarizing Ca2+-dependent K+ current than sumatriptan. In anesthetized pigs, F 11356 elicited highly cranioselective, more potent (from 0.16 μg/kg i.v.) and greater carotid vasoconstriction than tryptamine derivatives. Decreases in carotid blood flow were observed in conscious dogs from 0.63 mg/kg oral F 11356 in the absence of changes in heart rate or behavior. Oral activity was confirmed when hypothermic responses were elicited in guinea pigs (ED50 = 1.6 mg/kg), suggesting that F 11356 also accesses the brain. F 11356 thus is a selective, high-potency agonist at 5- HT(1B/1D) receptors, which distinguishes itself from tryptamine and derivatives in exerting high intrinsic activity at these receptors in vascular and neuronal models relevant to migraine.

Original languageEnglish (US)
Pages (from-to)83-95
Number of pages13
JournalJournal of Pharmacology and Experimental Therapeutics
Volume290
Issue number1
StatePublished - Jul 1 1999
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    John, G. W., Pauwels, P. J., Perez, M., Halazy, S., Le Grand, B., Verscheure, W., Valentin, J. P., Palmier, C., Wurch, T., Chopin, P., Marien, M., Kleven, M. S., Koek, W., Assie, M. B., Carilla-Durand, E., Tarayre, J. P., & Colpaert, F. C. (1999). F 11356, a novel 5-hydroxytryptamine (5-HT) derivative with potent, selective, and unique high intrinsic activity at 5-HT(1B/1D) receptors in models relevant to migraine. Journal of Pharmacology and Experimental Therapeutics, 290(1), 83-95.