caa a22 4500 469079274 CHVBK 20180323132945.0 cr unu---uuuuu 170328e19920301xx s 000 0 eng 10.1007/BF00168684 doi (NATIONALLICENCE)springer-10.1007/BF00168684 Agonist/antagonist interactions with cloned human 5-HT1A receptors: variations in intrinsic activity studied in transfected HeLa cells [Elektronische Daten] [Hendrikus Boddeke, Annick Fargin, John Raymonde, Philippe Schoeffter, Daniel Hoyer] Summary: The characteristics of 5-HT1A-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-HT1A 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-HT1A 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 216-525 (Seiler et al. 1991) acted as silent and potent antagonists. Marked differences were observed in the responses mediated in the two cell lines. EC50 values 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-HT1A receptor models (e.g. inhibition of adenylate cyclase in calf hippocampus). Further, a variety of compounds (ipsapirone, buspirone, spiroxatrine, MDL 73005) acted as agonists in HA 6 cells, whereas they behaved as silent antagonists in HA 7 cells (which express fewer receptors). By contrast, KB values for antagonists were comparable in HA 6 and HA 7 cells. The present data show that EC50 values 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-HT1A 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. Springer-Verlag, 1992 Human 5-HT1A receptors nationallicence Agonism nationallicence Antagonism nationallicence Intrinsic activity nationallicence Boddeke Hendrikus Preclinical Research, 360/604, SANDOZ Pharma Ltd, CH-4002, Basel, Switzerland aut Fargin Annick Department of Medicine, Howard Hughes Medical Institute, Duke University Medical Center, 27710, Durham, NC, USA aut Raymonde John Department of Medicine, Howard Hughes Medical Institute, Duke University Medical Center, 27710, Durham, NC, USA aut Schoeffter Philippe Preclinical Research, 360/604, SANDOZ Pharma Ltd, CH-4002, Basel, Switzerland aut Hoyer Daniel Preclinical Research, 360/604, SANDOZ Pharma Ltd, CH-4002, Basel, Switzerland aut Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 345/3(1992-03-01), 257-263 0028-1298 345:3<257 1992 345 210 https://doi.org/10.1007/BF00168684 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00168684 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Boddeke Hendrikus Preclinical Research, 360/604, SANDOZ Pharma Ltd, CH-4002, Basel, Switzerland aut NATIONALLICENCE 700 1- Fargin Annick Department of Medicine, Howard Hughes Medical Institute, Duke University Medical Center, 27710, Durham, NC, USA aut NATIONALLICENCE 700 1- Raymonde John Department of Medicine, Howard Hughes Medical Institute, Duke University Medical Center, 27710, Durham, NC, USA aut NATIONALLICENCE 700 1- Schoeffter Philippe Preclinical Research, 360/604, SANDOZ Pharma Ltd, CH-4002, Basel, Switzerland aut NATIONALLICENCE 700 1- Hoyer Daniel Preclinical Research, 360/604, SANDOZ Pharma Ltd, CH-4002, Basel, Switzerland aut NATIONALLICENCE 773 0- Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 345/3(1992-03-01), 257-263 0028-1298 345:3<257 1992 345 210 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer