title: How selective is GR 43175? Interactions with functional 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors.
abstract: GR 43175 (3-[2-dimethylamino]ethyl-N-methyl-1 H-indole-5 methane sulphonamide) is a novel 5-HT1-like receptor-selective agonist which was reported to be active in the treatment of migraine attacks. The effects of the compound were investigated in radioligand binding studies and in functional models for 5-HT1A, 5-HT1B, and 5-HT1D receptors (inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus, rat and calf substantia nigra, respectively) and 5-HT1C receptors (stimulation of inositol phosphate production in pig choroid plexus). GR 43175 displayed the following order of affinity for 5-HT recognition sites (pKD values, -log mol/l, in parentheses): 5-HT1D (7.54) greater than 5-HT1B (6.35) greater than 5-HT1A (6.13) much greater than 5-HT1C (4.13) greater than 5-HT2 (3.67). The same order of potency was observed at functional 5-HT1 receptors, at which GR 43175 acted as a full agonist, with the exception of the 5-HT1C receptor, where the compound was a weak antagonist (pEC50 or pKB values, -log mol/l, in parentheses): 5-HT1D (6.28) greater than 5-HT1B (6.03) greater than 5-HT1A (5.57) much greater than 5-HT1C (4.25). The present data show that GR 43175 interacts preferentially as an agonist with 5-HT1B and 5-HT1D receptors. Since 5-HT1B receptors have not yet been identified in human brain, it seems possible that it is the 5-HT1D receptor which is relevant to the reported antimigraine effects of this compound.
authors.affiliation: Preclinical Research, Sandoz Ltd., Basel, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Schoeffter
authors.forename: D
authors.initials: D
authors.lastname: Hoyer
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D015290:Second Messenger Systems / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D018170:Sumatriptan; D013552:Swine
chemical_list: D007211:Indoles; D011985:Receptors, Serotonin; D013449:Sulfonamides; D012701:Serotonin; D018170:Sumatriptan