Functional effects of the 5-HT1D receptor antagonist GR 127,935 at human 5-HT1D alpha, 5-HT1D beta, 5-HT1A and opossum 5-HT1B receptors.
The functional activity and selectivity of the novel 5-HT1D receptor antagonist GR 127,935 (2'-methyl-4'(5-methyl-1,2,4 oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide) was investigated at cloned human 5-HT1A, 5-HT1D alpha, 5-HT1D beta and opossum kidney (OK) 5-HT1B receptor sites. 5-HT1 receptor-mediated activity was studied by measuring the inhibition of forskolin-induced cAMP formation in cell lines expressing these receptors (Bmax (fmol/mg protein): human epitheloid carcinoma HeLa/5-HT1A: 1285, OK/5-HT1B: 52, Chinese hamster ovary CHO-K1/5-HT1D alpha: 181 and CHO-K1/5-HT1D beta: 685). GR 127,935 did not show 5-HT1D beta receptor-mediated agonist activity in permanently transfected CHO-K1 cells, whereas at submicromolar and higher concentrations intrinsic agonist activity was observed in HeLa/5-HT1A,OK/5-HT1B and CHO-K1/5-HT1D alpha cells. GR 127,935 showed potent (KB value: 1.3 nM) and silent antagonism at CHO-K1/5-HT1D beta receptor sites. The antagonist activity of 1 microM of GR 127,935 at CHO-K1/5-HT1D alpha and OK/5-HT1B receptor sites was only partial and less pronounced. This contrasts with the silent antagonism of methiothepin at the 5-HT1D alpha (KB value = 11.8 nM), 5-HT1D beta (KB value = 6.9 nM) and 5-HT1B (KB value = 49.3 nM) receptor subtypes. GR 127,935, when tested at 10 microM, was found to be a weak and partial antagonist of HeLa/5-HT1A receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Pauwels
P J
PJ
Laboratory of Cellular Neurobiology, Centre de Recherche Pierre Fabre, Castres, France.
Palmier
C
C
D000818:Animals; D016466:CHO Cells; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008719:Methiothepin / Q000494:pharmacology; D009893:Opossums; D010069:Oxadiazoles / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000145:classification / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013134:Spiperone / Q000494:pharmacology; D014162:Transfection
D010069:Oxadiazoles; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D005576:Colforsin; C090701:GR 127935; D013134:Spiperone; D008719:Methiothepin; D000242:Cyclic AMP