Allosteric Potentiators of the Metabotropic Glutamate Receptor 2 (mGlu2). Part 1. Identification and Synthesis of Phenyl-tetrazolyl Acetophenones.
ABSTRACT We have identified and synthesized a series of aryl-tetrazoyl acetophenones as positive allosteric potentiators of the metabotropic glutamate receptor 2. Structure activity relationship studies directed toward improving the potency and level of potentiation led to the discovery of 22 (EC(50)=93nM, 128% potentiation).
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- "These compounds show selectivity for mGluR2 compared with other mGluR subtypes (Johnson et al, 2003, 2005; Schaffhauser et al, 2003; Galici et al, 2006) and bind at an allosteric site on the receptor to potentiate glutamateinduced activation of the receptor (Schaffhauser et al, 2003). mGluR2 PAMs have some of the same behavioral effects as mGlu2/3 agonists in animal tests used to assess anxiolytic and antipsychotic activity (Johnson et al, 2003, 2005; Schaffhauser et al, 2003; Pinkerton et al, 2004; Bonnefous et al, 2005; Galici et al, 2005, 2006; Govek et al, 2005; Benneyworth et al, 2007). These findings are consistent with recent reports showing that mGluR2, but not mGluR3, mediates the actions of the mGluR2/3 agonist LY379268 in mouse tests predictive of antipsychotic activity (Woolley et al, 2008). "
ABSTRACT: Metabotropic glutamate receptor 2/3 (mGluR2/3) agonists were shown previously to nonselectively decrease both cocaine- and food-maintained responding in rats. mGluR2 positive allosteric modulators (PAMs) may represent improved therapeutic compounds because of their modulatory properties and higher selectivity for mGluR2. We analyzed the effects of the selective, brain penetrant, and systemically active mGluR2 PAM potassium 3'-([(2-cyclopentyl-6-7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl)biphenyl l-4-carboxylate (BINA) and the mGluR2/3 agonist LY379268 on intravenous cocaine self-administration and cocaine-seeking behavior in rats that had short (1 h, ShA) or long (6 h, LgA) access to cocaine. The effects of BINA on food responding and food-seeking behavior were also analyzed. Finally, we examined the effects of BINA on brain reward function and cocaine-induced reward enhancement using the intracranial self-stimulation procedure. BINA decreased cocaine self-administration in both ShA and LgA rats, with no effect on food self-administration. Alternatively, LY379268 nonselectively decreased both cocaine and food self-administration. BINA decreased cue-induced reinstatement of cocaine seeking with no effect on food seeking. The cocaine-induced enhancement of brain reward function was blocked by BINA, although the highest doses of BINA decreased brain reward function when administered alone, suggesting additive, rather than interactive, effects of BINA and cocaine. In conclusion, BINA attenuated the reinforcing and counteracted the reward-enhancing effects of cocaine and decreased cue-induced cocaine-seeking behavior, without affecting behaviors motivated by food reinforcement. The higher selectivity of BINA compared with an mGluR2/3 agonist for drug- vs food-motivated behaviors suggests a therapeutic role for mGluR2 PAMs for the treatment of cocaine addiction and possibly other drugs of abuse.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2010; 35(10):2021-36. DOI:10.1038/npp.2010.82 · 7.83 Impact Factor
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ABSTRACT: We have identified and synthesized a series of 4-thiopyridyl acetophenones as positive allosteric potentiators of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward replacement of the tetrazole in the initial lead led to the discovery of 16 (EC(50)=340 nM), which showed improved brain penetration over the initial lead.Bioorganic & Medicinal Chemistry Letters 01/2005; 14(23):5867-72. DOI:10.1016/j.bmcl.2004.09.028 · 2.33 Impact Factor
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ABSTRACT: This article describes recent medicinal chemistry progress toward selective potentiators of the metabotropic glutamate receptor 2 (mGluR2). Groups at Lilly and Merck have identified new classes of potentiators that exhibit selectivity for mGluR2 over the seven other subtypes of mGluRs. Structure-activity relationships as well as pharmacokinetic properties and in vivo activity are reviewed.Current Topics in Medicinal Chemistry 02/2005; 5(9):869-84. DOI:10.2174/1568026054750281 · 3.45 Impact Factor