Allosteric Potentiators of the Metabotropic Glutamate Receptor 2 (mGlu2). Part 1. Identification and Synthesis of Phenyl-tetrazolyl Acetophenones.
Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA. Bioorganic & Medicinal Chemistry Letters
(Impact Factor: 2.42).
12/2004; 14(21):5329-32. DOI: 10.1016/j.bmcl.2004.08.020
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 = 93 nM, 128% potentiation). 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 = 93 nM, 128% potentiation).
Available from: Derek K Tracy
- "As growing evidence from animal studies has emphasised the critical role of the mGlu2 receptor in mediating the clinical effects of this group of compounds [118, 119], potent selectivity for this subtype might yield increased efficacy. Notably, strong potential for antipsychotic action has been demonstrated for the two major prototypes, LY487379 and Biphenylindanone A (BINA), resembling results of the aforementioned orthosteric mGlu2/3 agonists [120–122]. "
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ABSTRACT: The dopamine hypothesis of schizophrenia remains the primary theoretical framework for the pharmacological treatment of the disorder. Despite various lines of evidence of dopaminergic abnormalities and reasonable efficacy of current antipsychotic medication, a significant proportion of patients show suboptimal treatment responses, poor tolerability, and a subsequent lack of treatment concordance. In recent decades, intriguing evidence for the critical involvement of other neurotransmitter systems in the pathophysiology of schizophrenia has emerged, most notably of dysfunctions within the glutamate pathways. Consequently, the glutamate synapse has arisen as a promising target for urgently needed novel antipsychotic compounds-particularly in regards to debilitating negative and cognitive symptoms poorly controlled by currently available drugs. In this paper, recent findings integrating glutamatergic and dopaminergic abnormalities in schizophrenia and their implications for novel pharmacological targets are discussed. An overview of compounds in various stages of development is given: drugs enhancing NMDA receptor function as well as metabotropic glutamate receptor (mGluR) agonist and positive allosteric modulators (PAMs) are emphasised. Together with other agents more indirectly affecting glutamatergic neurotransmission, their potential future role in the pharmacotherapy of schizophrenia is critically evaluated.
Available from: P. Jeffrey Conn
- "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). "
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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.
Available from: Shigeyuki Chaki
- "Another series of compounds results from 4’-alkoxyacetophenone derivatives, and is typified by compound 1. Compound 1 is a selective mGlu2 receptor potentiator (300 nM) with no allosteric activities against mGlu1, 3, 4, 5, 7 or 8 [106, 107]. "
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ABSTRACT: Metabotropic glutamate receptors (mGlu receptors) have emerged as new therapeutic targets for psychiatric disorders, such as schizophrenia, depression and anxiety with their regulatory roles in glutamatergic transmissions. To date, several ligands selective for each mGlu receptor have been synthesized, and pharmacological significances of these ligands have been demonstrated in animal models. Among them, mGlu2/3 receptor agonists have been proven to be effective for treating schizophrenia and anxiety disorders in clinical studies, which may prove utilities of mGlu receptor ligands for the treatment of psychiatric disorders. This article reviews recent advances in development of each mGlu receptor ligands and their therapeutic potential.
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