Abstract
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 F2α(PGF2α). However, even in the presence of PGF2α (3 × 10−7 M), LY344864 did not contract the rabbit saphenous vein in concentrations well in excess of its 5-HT1F receptor affinity (pKi = 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 PGF2α. 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.
Footnotes
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Send reprint requests to: Dr. Marlene L. Cohen, Eli Lilly and Co., Drop Code 0520, Building 48/2, Indianapolis, IN 46285. E-mail:cohenml{at}lilly.com
- Abbreviations:
- 5-HT
- 5-hydroxytryptamine or serotonin
- SSOFRA
- selective 5-HT1F receptor agonists
- PGF2α
- prostaglandin F2α
- Received August 27, 1998.
- Accepted March 1, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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