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-HT1B/1D receptors. F 11356 has subnanomolar affinity for cloned human and nonhuman 5-HT1B and 5-HT1Dreceptors, 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 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-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.
Footnotes
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Send reprint requests to: Dr. G. W. John, Centre de Recherche Pierre FABRE, 17 Ave. Jean Moulin, 81106 Castres Cedex, France. E-mail: gareth.john{at}pierre-fabre.com
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↵1 Part of this work was presented at the IUPHAR meeting held in München, Germany, July 1998, and has been published in abstract form (John et al., 1998a, b; Pauwels et al., 1998a).
- Abbreviations:
- 5-HT
- 5-hydroxytryptamine (serotonin)
- DHE
- dihydroergotamine
- F 11356
- 4-[4-[2-(2-aminoethyl)-1H-indol-5-yloxyl]acetyl]piperazinyl-1-yl]benzonitrile HCl
- GTPγS
- guanosine-5′-O-(3-thio)triphosphate
- GR 127935
- 2′-methyl-4′-(5-methyl[1,2,4]oxadiozol-3-yl)biphenyl-4-carboxylic acid[4-methoxy-3-(4-methyl piperazin-1-yl)phenyl]amide 2 HCl
- cAMP
- cyclic AMP
- l-NAME
- Nω-nitro-l-arginine methyl ester
- U 46619
- 9,11-dideoxy-9α,11α-methanoepoxy PGF2α
- Received December 14, 1998.
- Accepted March 4, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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