A series of 5-alkyltryptamines (6) and the corresponding conformationally constrained analogues (8) have been synthesized. The structure-activity relationships (SAR) at the 5-position of the indole skeleton and the et...
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A series of 5-alkyltryptamines (6) and the corresponding conformationally constrained analogues (8) have been synthesized. The structure-activity relationships (SAR) at the 5-position of the indole skeleton and the ethylamine side chain have been studied. Functional activities were assessed using isolated rabbit saphenous vein. Potent, selective ligands were found (6e, K-i 2.5 nM, 5-HT1B/5-HT1D 125-fold) that have potential for treating acute migraine. (C) 2000 Elsevier Science Ltd. All rights reserved.
A convenient functional assay for 5HT2a and 5HT2c receptors is reported utilizing the bioluminescent aequorin to detect intracellular calcium changes. Using this assay, the pharmacological properties of many 5HT ligan...
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A convenient functional assay for 5HT2a and 5HT2c receptors is reported utilizing the bioluminescent aequorin to detect intracellular calcium changes. Using this assay, the pharmacological properties of many 5HT ligands can be determined in a 96-well format. The data indicate that the aequorin detection method is superior to the inositol phosphate assay with regard to speed and scope. This system is also appropriate for kinetic studies of receptor desensitization. We showed that the human 5HT2c receptor desensitizes in a biphasic manner, with a fast desensitization of approximately 90% of the total response occurring within 15 minutes while the remaining 10% response remains for at least 3 hours.
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 ag...
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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.
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