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Title: Alniditan, a new 5-hydroxytryptamine(1D) agonist and migraine-abortive agent: Ligand-binding properties of human 5-hydroxytryptamine(1D alpha), human 5-hydroxytryptamine(1D beta), and calf 5-hydroxytryptamine(1D) receptors investigated with [H-3]5-hydroxytryptamine and [H-3]Alniditan
Authors: Leysen, JE ×
Gommeren, W
Heylen, L
Luyten, WHML
VandeWeyer, I
Vanhoenacker, P
Haegeman, G
Schotte, Anne-Marie
VanGompel, P
Wouters, M
Lesage, AS #
Issue Date: Dec-1996
Publisher: Williams & wilkins
Series Title: Molecular Pharmacology vol:50 issue:6 pages:1567-1580
Abstract: Alniditan is a new migraine-abortive agent. It is a benzopyran derivative and therefore structurally unrelated to sumatriptan and other indole-derivatives and to ergoline derivatives. The action of sumatriptan is thought to be mediated by 5-hydroxy-tryptamine (5-HT)(1D)-type receptors. We investigated the receptor-binding profile in vitro of alniditan compared with sumatriptan and dihydroergotamine for 28 neurotransmitter receptor subtypes, several receptors for peptides and lipid-derived factors, ion channel-binding sites, and monoamine transporters. Alniditan revealed nanomolar affinity for calf substantia nigra 5-HT1D and for cloned h5-HT1D alpha, h5-HT1D beta, and h5-HT1A receptors (K-i = 0.8, 0.4, 1.1, and 3.8 nM, respectively). Alniditan was more potent than sumatriptan at 5-HT1D-type and 5-HT1A receptors. Alniditan showed moderate-to-low or no affinity for other investigated receptors; sumatriptan showed additional binding to 5-HT1F receptors. Dihydroergotamine had a much broader profile with high affinity for several 5-HT, adrenergic and dopaminergic receptors. In signal transduction assays using cells expressing recombinant h5-HT1D alpha, h5-HT1D beta, or h5-HT1A receptors, alniditan (like 5-HT) was a full agonist for inhibition of stimulated adenylyl cyclase (IC50 = 1.1, 1.3, and 74 nM, respectively, for alniditan). Therefore, in functional assays, the potency of alniditan was much higher at 5-HT1D receptors than at 5-HT1A receptors. We further compared the properties of [H-3]alniditan, as a new radioligand for 5-HT1D-type receptors, with those of [H-3]5-HT in membrane preparations of calf substantia nigra, C6 glioma cells expressing h5-HT1D alpha, and L929 cells expressing h5-HT1D beta receptors. [H-3]Alniditan revealed very rapid association and dissociation binding kinetics and showed slightly higher affinity (K-d = 1-2 nM) than [H-3]5-HT. We investigated 25 compounds for inhibition of [H-3]alniditan and [H-3]5-HT binding in the three membrane preparations; K-i values of the radioligands were largely similar, although some subtle differences appeared. Most compounds did not differentiate between 5-HT1D alpha and 5-HT1D beta receptors, except methysergide, ritanserin, ocaperidone, risperidone, and ketanserin, which showed 10-60-fold higher affinity for the 5-HT1D alpha receptor. The K-i values of the compounds obtained with 5-HT1D receptors in calf substantia nigra indicated that these receptors are of the 5-HT1D alpha-type. We demonstrated that alniditan is a potent agonist at h5-HT1D alpha and h5-HT1D beta receptors; its properties probably underlie its cranial vasoconstrictive and antimigraine properties.
ISSN: 0026-895X
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical Residents Dentistry
× corresponding author
# (joint) last author

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