1.
Alniditan, a novel
migraine abortive agent, is a potent 5-HT1B/
5-HT1D receptor agonist of nM affinity. We compared the agonistic properties of
alniditan,
sumatriptan and
dihydroergotamine on the cloned human
5-HT1B receptor expressed at 200 fmol mg(-1)
protein (Bmax) in non-induced L929sA cells, at 740 fmol mg(-1)
protein in HEK 293 and at 2300 fmol mg(-1)
protein in mIFNbeta-induced L929sA cells, and on the human cloned
5-HT1D receptor expressed in C6
glioma cells (Bmax 780 fmol mg(-1)
protein). 2.
Sodium butyrate treatment increased the expression level of human (h)5-HT1B receptors in HEK 293 cells and h5-HT1D receptors in C6
glioma cells approximately 3 fold, the binding affinities of [3H]-5-HT and [3H]-
alniditan were unaffected. 3. Agonistic properties were evaluated based on inhibition of
cyclic AMP accumulation in the cells after stimulation of
adenylyl cyclase by
forskolin or
isoproterenol.
Alniditan,
sumatriptan and
dihydroergotamine were full agonists at the hS-HT1B receptor (IC50 values were 1.7, 20 and 2 nM, respectively in HEK 293 cells) and hS-HT1D receptors (IC50 values of 1.3, 2.6 and 2.2 nM, respectively). At the h5-HT1B receptor the agonist potency of the compounds slightly increased with higher receptor density. The opposite was seen for antagonists (
ocaperidone,
risperidone and
ritanserin). 4. This comparative study demonstrated that
alniditan was 10 times more potent than
sumatriptan at the h5-HT1B receptor, and twice as potent at the h5-HT1D receptor.
Dihydroergotamine was more potent an agonist at the h5-HT1B receptor when expressed at high and low level in L929sA cells (but not in HEK 293 cells), and was less potent at the hS-HT1D receptor.