Vol. 290, Issue 1, 83-95, July 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 Migraine¹

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

Centre de Recherche Pierre Fabre, Castres Cedex, France

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.