title: Alniditan, a new 5-hydroxytryptamine1D agonist and migraine-abortive agent: ligand-binding properties of human 5-hydroxytryptamine1D alpha, human 5-hydroxytryptamine1D beta, and calf 5-hydroxytryptamine1D receptors investigated with [3H]5-hydroxytryptamine and [3H]alniditan.
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-hydroxytryptamine (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 (Ki = 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 [3H]alniditan, as a new radioligand for 5-HT1D-type receptors, with those of [3H]5-HT in membrane preparations of calf substantia nigra, C6 glioma cells expressing h5-HT1D alpha, and L929 cells expressing h5-HT1D beta receptors. [3H]Alniditan revealed very rapid association and dissociation binding kinetics and showed slightly higher affinity (Kd = 1-2 nM) than [3H]5-HT. We investigated 25 compounds for inhibition of [3H]alniditan and [3H]5-HT binding in the three membrane preparations; Ki 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 Ki values of the compounds obtained with 5-HT1D receptors in calf substantia nigra indicated that these receptors are of the 5-HT1D beta-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.
authors.affiliation: Department of Biochemical Pharmacology, Janssen Research Foundation, Beerse, Belgium.
authors.forename: J E
authors.initials: JE
authors.lastname: Leysen
authors.forename: W
authors.initials: W
authors.lastname: Gommeren
authors.forename: L
authors.initials: L
authors.lastname: Heylen
authors.forename: W H
authors.initials: WH
authors.lastname: Luyten
authors.forename: I
authors.initials: I
authors.lastname: Van de Weyer
authors.forename: P
authors.initials: P
authors.lastname: Vanhoenacker
authors.forename: G
authors.initials: G
authors.lastname: Haegeman
authors.forename: A
authors.initials: A
authors.lastname: Schotte
authors.forename: P
authors.initials: P
authors.lastname: Van Gompel
authors.forename: R
authors.initials: R
authors.lastname: Wouters
authors.forename: A S
authors.initials: AS
authors.lastname: Lesage
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002417:Cattle; D003001:Cloning, Molecular; D005910:Glioma / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008881:Migraine Disorders / Q000517:prevention & control*; D011437:Propylamines / Q000494:pharmacology*; D011485:Protein Binding; D011743:Pyrimidines / Q000494:pharmacology*; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction; D014316:Tritium; D014407:Tumor Cells, Cultured; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D001578:Benzopyrans; D011437:Propylamines; D011743:Pyrimidines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014662:Vasoconstrictor Agents; D014316:Tritium; C100822:alniditan