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

Alniditan is a new migraine-abortive agent. It is a benzopyran derivat ive and therefore structurally unrelated to sumatriptan and other indo le-derivatives and to ergoline derivatives. The action of sumatriptan is thought to be mediated by 5-hydroxy-tryptamine (5-HT)(1D)-type rece ptors. We investigated the receptor-binding profile in vitro of alnidi tan compared with sumatriptan and dihydroergotamine for 28 neurotransm itter receptor subtypes, several receptors for peptides and lipid-deri ved factors, ion channel-binding sites, and monoamine transporters. Al niditan revealed nanomolar affinity for calf substantia nigra 5-HT1D a nd 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; suma triptan showed additional binding to 5-HT1F receptors. Dihydroergotami ne had a much broader profile with high affinity for several 5-HT, adr energic and dopaminergic receptors. In signal transduction assays usin g 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 alni ditan was much higher at 5-HT1D receptors than at 5-HT1A receptors. We further compared the properties of [H-3]alniditan, as a new radioliga nd for 5-HT1D-type receptors, with those of [H-3]5-HT in membrane prep arations of calf substantia nigra, C6 glioma cells expressing h5-HT1D alpha, and L929 cells expressing h5-HT1D beta receptors. [H-3]Alnidita n revealed very rapid association and dissociation binding kinetics an d showed slightly higher affinity (K-d = 1-2 nM) than [H-3]5-HT. We in vestigated 25 compounds for inhibition of [H-3]alniditan and [H-3]5-HT binding in the three membrane preparations; K-i values of the radioli gands 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, risperid one, 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 pot ent agonist at h5-HT1D alpha and h5-HT1D beta receptors; its propertie s probably underlie its cranial vasoconstrictive and antimigraine prop erties.