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

H.W.G.M. Boddeke, A. Fargin, J.R. Raymond, P. Schoeffter, D. Hoyer

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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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