Inverse agonism and neutral antagonism at wild-type and constitutively active mutant delta opioid receptors
| Autor: | Brigitte L. Kieffer, Helmut Schmidhammer, Dominique Filliol, Larry H Lazarus, Peter W. Schiller, Petra Tryoen-Toth, Katia Befort, Fabien Decaillot |
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| Přispěvatelé: | Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Narcotic Antagonists
MESH: Piperazines MESH: Enkephalin Leucine (+)-Naloxone Ligands Piperazines MESH: Dose-Response Relationship Drug MESH: Benzamides 0302 clinical medicine MESH: Alkaline Phosphatase MESH: Structure-Activity Relationship MESH: Dipeptides Receptors Opioid delta MESH: Receptors Opioid delta MESH: Ligands Receptor 0303 health sciences Chemistry Dipeptides Naltrexone 3. Good health MESH: Guanosine 5'-O-(3-Thiotriphosphate) Benzamides Molecular Medicine SNC-80 MESH: Naltrexone MESH: Narcotic Antagonists Enkephalin Leucine medicine.drug Agonist MESH: Mutation medicine.drug_class Stereochemistry Cell Line δ-opioid receptor Structure-Activity Relationship 03 medical and health sciences Naltrindole medicine Humans Inverse agonist 030304 developmental biology Pharmacology MESH: Humans Dose-Response Relationship Drug [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology Alkaline Phosphatase MESH: Cell Line Naltriben Guanosine 5'-O-(3-Thiotriphosphate) Mutation 030217 neurology & neurosurgery |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics Journal of Pharmacology and Experimental Therapeutics, American Society for Pharmacology and Experimental Therapeutics, 2005, 313 (1), pp.410-21. ⟨10.1124/jpet.104.077321⟩ |
| ISSN: | 0022-3565 1521-0103 |
| Popis: | International audience; The delta opioid receptor modulates nociceptive and emotional behaviors. This receptor has been shown to exhibit measurable spontaneous activity. Progress in understanding the biological relevance of this activity has been slow, partly due to limited characterization of compounds with intrinsic negative activity. Here, we have used constitutively active mutant (CAM) delta receptors in two different functional assays, guanosine 5'-O-(3-thio)triphosphate binding and a reporter gene assay, to test potential inverse agonism of 15 delta opioid compounds, originally described as antagonists. These include the classical antagonists naloxone, naltrindole, 7-benzylidene-naltrexone, and naltriben, a new set of naltrindole derivatives, H-Tyr-Tic-Phe-Phe-OH (TIPP) and H-Tyr-TicPsi[CH2N]Cha-Phe-OH [TICP(Psi)], as well as three 2',6'-dimethyltyrosine-1,2,3,4-tetrahydroquinoline-3-carboxylate (Dmt-Tic) peptides. A reference agonist, SNC 80 [(+)-4-[(alphaR)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide], and inverse agonist, ICI 174864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu), were also included. In a screen using wild-type and CAM M262T delta receptors, naltrindole (NTI) and close derivatives were mostly inactive, and TIPP behaved as an agonist, whereas Dmt-Tic-OH and N,N(CH3)2-Dmt-Tic-NH2 showed inverse agonism. The two latter compounds showed negative activity across 27 CAM receptors, suggesting that this activity was independent from the activation mechanism. These two compounds also exhibited nanomolar potencies in dose-response experiments performed on wild-type, M262T, Y308H, and C328R CAM receptors. TICP(Psi) exhibited strong inverse agonism at the Y308H receptor. We conclude that the stable N,N(CH3)2-Dmt-Tic-NH2 compound represents a useful tool to explore the spontaneous activity of delta receptors, and NTI and novel derivatives behave as neutral antagonists. |
| Databáze: | OpenAIRE |
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