title: Human native kappa opioid receptor functions not predicted by recombinant receptors: Implications for drug design.
abstract: If activation of recombinant G protein-coupled receptors in host cells (by drugs or other ligands) has predictive value, similar data must be obtained with native receptors naturally expressed in tissues. Using mouse and human recombinant κ opioid receptors transfected into a host cell, two selectively-acting compounds (ICI204448, asimadoline) equi-effectively activated both receptors, assessed by measuring two different cell signalling pathways which were equally affected without evidence of bias. In mouse intestine, naturally expressing κ receptors within its nervous system, both compounds also equi-effectively activated the receptor, inhibiting nerve-mediated muscle contraction. However, whereas ICI204448 acted similarly in human intestine, where κ receptors are again expressed within its nervous system, asimadoline was inhibitory only at very high concentrations; instead, low concentrations of asimadoline reduced the activity of ICI204448. This demonstration of species-dependence in activation of native, not recombinant κ receptors may be explained by different mouse/human receptor structures affecting receptor expression and/or interactions with intracellular signalling pathways in native environments, to reveal differences in intrinsic efficacy between receptor agonists. These results have profound implications in drug design for κ and perhaps other receptors, in terms of recombinant-to-native receptor translation, species-dependency and possibly, a need to use human, therapeutically-relevant, not surrogate tissues.
authors: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
authors: John
authors: J
authors: Broad
authors: Institut de Génomique Fonctionnelle, Dépt de Pharmacologie Moléculaire, UMR 5203 CNRS-U 661 INSERM, Univ Montpellier I &II, 141, 34094 Montpellier, France.
authors: Damien
authors: D
authors: Maurel
authors: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
authors: Victor W S
authors: VW
authors: Kung
authors: Tioga Pharmaceuticals, 9393 Towne Centre Drive, Suite 200, San Diego, California, USA.
authors: Gareth A
authors: GA
authors: Hicks
authors: Human Biology, TU München, D-85350 Freising-Weihenstephan, Germany.
authors: Michael
authors: M
authors: Schemann
authors: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
authors: Michael R
authors: MR
authors: Barnes
authors: Dept of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors: Terrence P
authors: TP
authors: Kenakin
authors: Institut de Génomique Fonctionnelle, Dépt de Pharmacologie Moléculaire, UMR 5203 CNRS-U 661 INSERM, Univ Montpellier I &II, 141, 34094 Montpellier, France.
authors: Sébastien
authors: S
authors: Granier
authors: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
authors: Gareth J
authors: GJ
authors: Sanger
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D011759:Pyrrolidines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013045:Species Specificity
chemical_list: D000081:Acetamides; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D011994:Recombinant Proteins; C092095:asimadoline