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

F 11356 (4-[4-[2-(2-aminoethyl)-1H-indol-5-yloxyl]acetyl]piperazinyl-1-yl]b enzonitrile) was designed to take advantage of the superior potency and eff icacy characteristics of 5-hydroxytryptamine (5-HT) compared with tryptamin e at 5-HT1B/1D receptors. F 11356 has subnanomolar affinity for cloned huma n and nonhuman 5-HT1B and 5-HT1D receptors, and its affinity for 5-HT1A and other 5-HT receptors, including the 5-ht(1F) subtype, is 50-fold lower and micromolar, respectively. In C6 cells expressing human 5-HT1B or human 5-H T1D receptors, F 11356 was the most potent compound in inhibiting forskolin -induced cyclic AMP formation (pD(2) = 8.9 and 9.6), and in contrast to try ptamine and derivatives, it produced maximal enhancement of [S-35]guanosine -5'-O-(3-thio)triphosphate binding equivalent to 5-HT. F 11356 was equipote nt to 5-HT (pD(2) = 7.1 versus 7.2) and more potent than tryptamine derivat ives in contracting rabbit isolated saphenous vein. In isolated guinea pig trigeminal ganglion neurons, F 11356 was more potent (pD(2) = 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 mu g/kg i.v.) and greater carotid v asoconstriction than tryptamine derivatives. Decreases in carotid blood flo w were observed in conscious dogs from 0.63 mg/kg oral F 11356 in the absen ce of changes in heart rate or behavior. Oral activity was confirmed when h ypothermic responses were elicited in guinea pigs (ED50 = 1.6 mg/kg), sugge sting that F 11356 also accesses the brain. F 11356 thus is a selective, hi gh-potency agonist at 5-HT1B/1D receptors, which distinguishes itself from tryptamine and derivatives in exerting high intrinsic activity at these rec eptors in Vascular and neuronal models relevant to migraine.