Inverse agonism and neutral antagonism at wild-type and constitutively active mutant delta opioid receptors.
Fiche publication
Date publication
avril 2005
Journal
The Journal of pharmacology and experimental therapeutics
Auteurs
Membres identifiés du Cancéropôle Est :
Dr TOTH Petra, Dr BEFORT Katia
Tous les auteurs :
Tryoen-Tóth P, Décaillot FM, Filliol D, Befort K, Lazarus LH, Schiller PW, Schmidhammer H, Kieffer BL
Lien Pubmed
Résumé
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.
Mots clés
Alkaline Phosphatase, metabolism, Benzamides, pharmacology, Cell Line, Dipeptides, pharmacology, Dose-Response Relationship, Drug, Enkephalin, Leucine, analogs & derivatives, Guanosine 5'-O-(3-Thiotriphosphate), pharmacology, Humans, Ligands, Mutation, Naltrexone, analogs & derivatives, Narcotic Antagonists, pharmacology, Piperazines, pharmacology, Receptors, Opioid, delta, agonists, Structure-Activity Relationship
Référence
J Pharmacol Exp Ther. 2005 Apr;313(1):410-21