TY - JOUR
T1 - 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
AU - John, Gareth W.
AU - Pauwels, Petrus J.
AU - Perez, Michel
AU - Halazy, Serge
AU - Le Grand, Bruno
AU - Verscheure, Wan
AU - Valentin, Jean Pierre
AU - Palmier, Christiane
AU - Wurch, Thierry
AU - Chopin, Philippe
AU - Marien, Marc
AU - Kleven, Mark S.
AU - Koek, Wouter
AU - Assie, Marie Bernadette
AU - Carilla-Durand, Elisabeth
AU - Tarayre, Jean Pierre
AU - Colpaert, Francis C.
PY - 1999/7/1
Y1 - 1999/7/1
N2 - 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.
AB - 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.
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M3 - Article
C2 - 10381763
AN - SCOPUS:0033006416
SN - 0022-3565
VL - 290
SP - 83
EP - 95
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 1
ER -