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.