AGONISTIC PROPERTIES OF ALNIDITAN, SUMATRIPTAN AND DIHYDROERGOTAMINE ON HUMAN 5-HT1B AND 5-HT1D RECEPTORS EXPRESSED IN VARIOUS MAMMALIAN-CELL LINES

1 Alniditan, a novel migraine abortive agent, is a potent 5-HT1B/5-HT1 D receptor agonist of nM affinity. We compared the agonistic propertie s of alniditan, sumatriptan and dihydroergotamine on the cloned human 5-HT1B receptor expressed at 200 fmol mg(-1) protein (B-max) in non-in duced L929sA cells, at 740 fmol mg(-1) protein in HEK 293 and at 2300 fmol mg(-1) protein in mIFN beta-induced L929sA cells, and on the huma n cloned 5-HT1D receptor expressed in C6 glioma cells (B-max 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 recept ors in C6 glioma cells approximately 3 fold, the binding affinities of [H-3]-5-HT and [H-3]-alniditan were unaffected. 3 Agonistic propertie s were evaluated based on inhibition of cyclic AMP accumulation in the cells after stimulation of adenylyl cyclase by forskolin or isoproter enol. Alniditan, sumatriptan and dihydroergotamine were full agonists at the h5-HT1B receptor (IC50 values were 1.7, 20 and 2 mM, respective ly in HEK 293 cells) and h5-HT1D receptors (IC50 values of 1.3, 2.6 an d 2.2 nM, respectively). At the h5-HT1B receptor the agonist potency o f the compounds slightly increased with higher receptor density. The o pposite was seen for antagonists (ocaperidone, risperidone and ritanse rin). 4 This comparative study demonstrated that alniditan was 10 time s more potent than sumatriptan at the h5-HT1B receptor, and twice as p otent at the h5-HT1D receptor. Dihydroergotamine was more potent an ag onist 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 h5 -HT1D receptor.