title: F 11356, a novel 5-hydroxytryptamine (5-HT) derivative with potent, selective, and unique high intrinsic activity at 5-HT1B/1D receptors in models relevant to migraine.
abstract: F 11356 (4-[4-[2-(2-aminoethyl)-1H-indol-5-yloxyl]acetyl]piperazinyl-1-yl] ben zonitrile) was designed to take advantage of the superior potency and efficacy characteristics of 5-hydroxytryptamine (5-HT) compared with tryptamine at 5-HT1B/1D receptors. F 11356 has subnanomolar affinity for cloned human and nonhuman 5-HT1B and 5-HT1D receptors, and its affinity for 5-HT1A and other 5-HT receptors, including the 5-ht1F subtype, is 50-fold lower and micromolar, respectively. In C6 cells expressing human 5-HT1B or human 5-HT1D 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 microgram/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-HT1B/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.
authors.affiliation: Centre de Recherche Pierre Fabre, Castres Cedex, France. gareth.john@pierre-fabre.com
authors.forename: G W
authors.initials: GW
authors.lastname: John
authors.forename: P J
authors.initials: PJ
authors.lastname: Pauwels
authors.forename: M
authors.initials: M
authors.lastname: Perez
authors.forename: S
authors.initials: S
authors.lastname: Halazy
authors.forename: B
authors.initials: B
authors.lastname: Le Grand
authors.forename: Y
authors.initials: Y
authors.lastname: Verscheure
authors.forename: J P
authors.initials: JP
authors.lastname: Valentin
authors.forename: C
authors.initials: C
authors.lastname: Palmier
authors.forename: T
authors.initials: T
authors.lastname: Wurch
authors.forename: P
authors.initials: P
authors.lastname: Chopin
authors.forename: M
authors.initials: M
authors.lastname: Marien
authors.forename: M S
authors.initials: MS
authors.lastname: Kleven
authors.forename: W
authors.initials: W
authors.lastname: Koek
authors.forename: M B
authors.initials: MB
authors.lastname: Assie
authors.forename: E
authors.initials: E
authors.lastname: Carilla-Durand
authors.forename: J P
authors.initials: JP
authors.lastname: Tarayre
authors.forename: F C
authors.initials: FC
authors.lastname: Colpaert
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced; D066298:In Vitro Techniques; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects*; D012501:Saphenous Vein / Q000187:drug effects; D013552:Swine; D012668:Trigeminal Ganglion / Q000166:cytology / Q000187:drug effects; D014363:Tryptamines
chemical_list: C470302:HTR1B protein, human; D009570:Nitriles; D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D014363:Tryptamines; D005576:Colforsin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C120143:donitriptan; D000242:Cyclic AMP