title: Agonistic properties of alniditan, sumatriptan and dihydroergotamine on human 5-HT1B and 5-HT1D receptors expressed in various mammalian cell lines.
abstract: 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.
authors.affiliation: Department of Biochemical Pharmacology, Janssen Research Foundation, Beerse, Belgium.
authors.forename: A S
authors.initials: AS
authors.lastname: Lesage
authors.forename: R
authors.initials: R
authors.lastname: Wouters
authors.forename: P
authors.initials: P
authors.lastname: Van Gompel
authors.forename: L
authors.initials: L
authors.lastname: Heylen
authors.forename: P
authors.initials: P
authors.lastname: Vanhoenacker
authors.forename: G
authors.initials: G
authors.lastname: Haegeman
authors.forename: W H
authors.initials: WH
authors.lastname: Luyten
authors.forename: J E
authors.initials: JE
authors.lastname: Leysen
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003001:Cloning, Molecular; D004087:Dihydroergotamine / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D051379:Mice; D011437:Propylamines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D018170:Sumatriptan / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D001578:Benzopyrans; D008024:Ligands; D011437:Propylamines; D011743:Pyrimidines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014662:Vasoconstrictor Agents; D004087:Dihydroergotamine; D018170:Sumatriptan; C100822:alniditan; D000262:Adenylyl Cyclases