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NEUROPHARMACOLOGY

Inverse Agonism and Neutral Antagonism at Wild-Type and Constitutively Active Mutant Delta Opioid Receptors

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, Illkirch, France (P.-T.T., D.F., K.B., B.L.K.); Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York (F.M.D.); Medicinal Chemistry Group, Laboratory of Computational Biology and Risk Analysis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (L.H.L.); Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Montreal, Quebec, Canada (P.W.S.); and Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria (H.S.)

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-Tic[CH₂N]Cha-Phe-OH [TICP()], as well as three 2',6'-dimethyltyrosine-1,2,3,4-tetrahydroquinoline-3-carboxylate (Dmt-Tic) peptides. A reference agonist, SNC 80 [(+)-4-[(R)--((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() 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.

Address correspondence to: Kieffer Brigitte, Institut de Génétique et Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, B.P. 1042, 67404 Illkirch Cedex, France. E-mail: briki{at}igbmc.u-strasbg.fr

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