Agonist/antagonist interactions with cloned human 5-HT(1A) receptors: Variations in intrinsic activity studied in transfected HeLa cells

Boddeke, H. W. G. M., Fargin, A., Raymond, J. R., Schoeffter, P. & Hoyer, D., 12-Nov-1992, In : Naunyn-Schmiedeberg's Archives of Pharmacology. 345, 3, p. 257-263 7 p.

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The characteristics of 5-HT(1A)-recognition sites and receptor-mediated release of intracellular calcium were established in two transfected HeLa cell lines (HA 6 and HA 7) expressing different levels of human 5-HT(1A) receptors (about 3000 and 500 fmol/mg protein, Fargin et al. 1989; 1991; Raymond et al. 1989). The pharmacological profiles of the binding (determined with [3H]8-OH-DPAT) and the calcium response (measured using Fura-2) were clearly of the 5-HT(1A) type. Compounds such as 5-HT, 5-CT and 8-OH-DPAT acted as full agonists on the calcium response in both HeLa cell lines. In addition, methiothepin, pindolol, NAN 190 and SDZ 21 6-525 (Seiler et al. 1991) acted as silent and potent antagonists. Marked differences were observed in the responses mediated in the two cell lines. EC50values of agonists (particularly 5-HT, 5-CT, flesinoxan and 8-OH-DPAT) were higher in HA 7 cells (up to 80-fold) than in other 5-HT(1A) receptor models (e. g. inhibition of adenylate cyclase in calf hippocampus). Further, a variety of compounds (ipsapirone, buspirone, spiroxatrine, MDL73005) acted as agonists in HA 6 cells, whereas they behaved as silent antagonists in HA 7 cells (which express fewer receptors). By contrast, K(B) values for antagonists were comparable in HA 6 and HA 7 cells. The present data show that EC50values and intrinsic activity for a given drug are subject to large variations depending on the number of receptors expressed in the target tissue. The results obtained in HA 6 cells are comparable with respect to both potency and efficacy to those observed in calf or mouse hippocampus (inhibition of forskolin stimulated adenylate cyclase), whereas the results obtained in HA 7 cells are similar to those reported in mouse cortex (which was suggested to represent an atypical subtype of the 5-HT(1A) receptor). Since the agonist activity of a given compound at the same receptor can vary markedly, the present data show that intrinsic activity is not only ligand-dependent but also varies with the receptor-effector system studied. In addition, there seems to be no simple way to make predictions about intrinsic activity, since that feature is model-dependent.
Original languageEnglish
Pages (from-to)257-263
Number of pages7
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Issue number3
Publication statusPublished - 12-Nov-1992


  • agonism, antagonism, human 5-HT(1A) receptors, intrinsic activity, 1 (2 methoxyphenyl) 4 (4 phthalimidobutyl)piperazine, 2 dipropylamino 8 hydroxytetralin, 4 [4 [4 (1,1,3 trioxo 2h 1,2 benzisothiazol 2 yl)butyl] 1 piperazinyl] 1h indole 2 carboxylic acid methyl ester, 5 carbamoyltryptamine, binospirone, buspirone, flesinoxan, ipsapirone, metitepine, pindolol, radioligand, serotonin, serotonin 1A receptor, serotonin agonist, serotonin antagonist, spiroxatrine, sumatriptan, agonist, article, calcium cell level, calcium transport, cell culture, concentration response, controlled study, drug activity, drug antagonism, drug potency, HeLa cell line, human, human cell, ligand binding, molecular cloning, priority journal

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