Vol. 290, Issue 3, 935-939, September 1999

5-Hydroxytryptamine_1F Receptors Do Not Participate in Vasoconstriction: Lack of Vasoconstriction to LY344864, a Selective Serotonin_1F Receptor Agonist in Rabbit Saphenous Vein

Marlene L. Cohen and Kathryn Schenck

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana

Recently, several novel approaches to the treatment of migraine have been advanced, including selective 5-hydroxytryptamine (or serotonin) 1B/1D (5-HT_1B/1D) receptor agonists such as sumatriptan and 5-HT_1F receptor agonists such as LY344864. Many 5-HT_1B/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 10⁴ M did not contract the rabbit saphenous vein. Furthermore, vascular contractions to sumatriptan were markedly augmented in the presence of prostaglandin F₂ (PGF₂). However, even in the presence of PGF₂ (3 × 10⁷ M), LY344864 did not contract the rabbit saphenous vein in concentrations well in excess of its 5-HT_1F receptor affinity (pK_i = 8.2). Only when concentrations exceeded those likely to activate 5-HT_1B and 5-HT_1D receptors (>10⁵ M) did modest contractile responses occur in the presence of PGF₂. 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-HT_1B and 5-HT_1D receptors, although contractile agonist potencies were not quantitatively similar to 5-HT_1B or 5-HT_1D 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-HT_1F receptors. These data support the contention that activation of 5-HT_1F receptors will not result in vascular contractile effects.