5-Hydroxytryptamine(1F) receptors do not participate in vasoconstriction: lack of vasoconstriction to LY344864, a selective serotonin(1F) receptor agonist in rabbit saphenous vein.

Recently, several novel approaches to the treatment of migraine have been advanced, including selective 5-hydroxytryptamine (or serotonin) 1B/1D (5-HT1B/1D) receptor agonists such as sumatriptan and 5-HT1F receptor agonists such as LY344864. Many 5-HT1B/1D receptor agonists have been identified based on their ability to produce cerebral vascular contraction, whereas LY344864 was identified as an inhibitor of trigeminal nerve-mediated dural extravasation. In our study, several triptan derivatives were compared with LY344864 for their ability to contract the rabbit saphenous vein, a tissue used in the preclinical identification of sumatriptan-related agonists. Sumatriptan, zolmitriptan, rizatriptan, and naratriptan all contracted the rabbit saphenous vein from baseline tone, whereas LY344864 in concentrations up to 10(-4) M did not contract the rabbit saphenous vein. Furthermore, vascular contractions to sumatriptan were markedly augmented in the presence of prostaglandin F-2 alpha (PGF(2 alpha)). However, even in the presence of PGF(2 alpha) (3 x 10(-7) M), LY344864 did not contract the rabbit saphenous vein in concentrations well in excess of its 5-HT1F receptor affinity (pK(i) = 8.2). Only when concentrations exceeded those likely to activate 5-HT1B and 5-HT1D receptors (>10(-5) M) did modest contractile responses occur in the presence of PGF(2 alpha). Use of these serotonergic agonists revealed a significant correlation between the contractile potency in the rabbit saphenous vein and the affinities of these agonists at 5-HT1B and 5-HT1D, receptors, although contractile agonist potencies were not quantitatively similar to 5-HT1B or 5-HT1D receptor affinities. In contrast, no significant correlation existed between the contractile potencies of these serotonergic agonists in the rabbit saphenous vein and their affinity at 5-HT1F receptors. These data support the contention that activation of 5-HT1F receptors will not result in vascular contractile effects.