Dimerization of sumatriptan as an efficient way to design a potent, centrally and orally active 5-HT1B agonist

A new bivalent ligand of formula 3 which results from the covalent coupling of two sumatriptan molecules with a p-xylyl spacer at the level of the sulfonamide nitrogen has been prepared and evaluated as a 5-HT1B/1D receptors agonist. In vitro experiments at 5-HT1B human cloned receptors (Ki = 0.64 n...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 1998-03, Vol.8 (6), p.675-680
Main Authors: PEREZ, M, PAUWELS, P. J, FOURRIER, C, CHOPIN, P, VALENTIN, J.-P, JOHN, G. W, MARIEN, M, HALAZY, S
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cell Line
Dimerization
Drug Design
Guinea Pigs
Humans
Medical sciences
Models, Chemical
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Rabbits
Receptor, Serotonin, 5-HT1B
Receptors, Serotonin - metabolism
Serotonin Receptor Agonists - chemical synthesis
Serotoninergic system
Sumatriptan - chemical synthesis
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Summary:A new bivalent ligand of formula 3 which results from the covalent coupling of two sumatriptan molecules with a p-xylyl spacer at the level of the sulfonamide nitrogen has been prepared and evaluated as a 5-HT1B/1D receptors agonist. In vitro experiments at 5-HT1B human cloned receptors (Ki = 0.64 nM; EC50 = 0.58 nM) and at the level of the contraction of the New Zealand white rabbit saphenous vein (pD2 = 6.6) demonstrate the superior potency of dimer 3 as a 5-HT1B receptor agonist when compared to sumatriptan or zolmitriptan. Interestingly enough, the new bivalent agonist 3 was found to induce hypothermia in the guineapig upon oral administration suggesting good oral activity and access to the brain.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(98)00090-0