THE ACTIVITY OF 5-HT1D RECEPTOR LIGANDS AT CLONED HUMAN 5-HT1D-ALPHA AND 5-HT1D-BETA RECEPTORS

The present study has examined the functional activity of the 5-HT1D r eceptor agonist, sumatriptan, and antagonists, GR127935 ethyl-[1,2,4]o xadiazol-3-yl)-biphenyl-4-carboxylic acid ethoxy-3-(4-methyl-piperazin -1-yl)-phenyl]-amide), GR55562 yl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl] benzamide), metergoline and methiothepin in HeLa cells, stably transfe cted with either 5-HT1D alpha or 5-HT1D beta receptor subtypes. Sumatr iptan, GR127935 and metergoline (each 0.01-1 mu M) behaved as agonists , producing a concentration-dependent inhibition of forskolin-stimulat ed adenosine 3',5'-cyclic monophosphate (cAMP) production at both 5-HT 1D alpha and 5-HT1D beta receptor subtypes (mean pIC(50) values of 8.4 and 8.3 for sumatriptan, 7.9 and 8.0 for GR127935, and 7.9 and 8.3 fo r metergoline, respectively). In contrast, GR55562 and methiothepin be haved as competitive 5-HT1D receptor antagonists and were devoid of an y agonist activity. GR55562 (10 mu M) caused a rightward displacement of the GR127935 and metergoline concentration-response curves. The ago nist activity of GR127935 and metergoline, observed in the present stu dy, contrasts with their recognised 5-HT1D receptor antagonist profile s in animal isolated tissue and behavioural models. Unlike GR127935, G R55562 behaved as a silent antagonist at the cloned human 5-HT1D alpha and 5-HT1D beta receptors in the study.