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 a ntagonist GR 127,935 (2'-methyl-4'-(5-methyl-1,2,4 oxadiazol-3-yl)-bip henyl-4-carboxylic acid methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-am ide) was investigated at cloned human 5-HT1A, 5-HT1D alpha, 5-HT1D bet a and opossum kidney (OK) 5-HT1B receptor sites. 5-HT1 receptor-mediat ed activity was studied by measuring the inhibition of forskolin-induc ed cAMP formation in cell lines expressing these receptors (B-max (fmo l/mg protein): human epitheloid carcinoma HeLa/5-HT1A : 1285, OK/5-HT1 B : 52, Chinese hamster ovary CHO-K1/5-HT1D alpha : 181 and CHO-K1/5-H T1D beta : 685). GR 127,935 did not show S-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 (K-B value: 1.3 nM) and silent antagonism at CHO -K1/5-HT1D beta receptor sites. The antagonist activity of 1 mu M of G R 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 antagonis m of methiothepin at the 5-HT1D alpha (K-B value = 11.8 nM), 5-HT1D be ta (K-B value = 6.9 nM) and 5-HT1B (K-B value = 49.3 nM) receptor subt ypes. GR 127,935, when tested at 10 mu M, was found to be a weak and p artial antagonist of HeLa/5-HT1A receptors. In conclusion, GR 127,935 is a potent and effective antagonist of cloned human 5-HT1D beta recep tor sites in transfected CHO-K1 cells but is only able to partially an tagonise CHO-K1/5-HT1D alpha, OK/5-HT1B and HeLa/5-HT1A receptor sites at micromolar concentrations.