6-methyl-2-(phenylethynyl)pyridine and Substance-Related-Disorders

Abundant evidence at the anatomical, electrophysiological, and molecular levels implicates metabotropic glutamate receptor subtype 5 (mGluR5) in addiction. Consistently, the effects of a wide range of doses of different mGluR5 negative allosteric modulators (NAMs) have been tested in various animal models of addiction. Here, these studies were subjected to a systematic review to find out if mGluR5 NAMs have a therapeutic potential that can be translated to the clinic.. Literature on consumption/self-administration and reinstatement of drug seeking as outcomes of interest published up to April 2015 was retrieved via PubMed. The review focused on the effects of systemic (i.p., i.v., s.c.) administration of the mGluR5 NAMs 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) and 2-Methyl-6-(phenylethynyl)pyridine (MPEP) on paradigms with cocaine, ethanol, nicotine, and food in rats.. MTEP and MPEP were found to reduce self-administration of cocaine, ethanol, and nicotine at doses ≥1mg/kg and 2.5mg/kg, respectively. Dose-response relationship resembled a sigmoidal curve, with low doses not reaching statistical significance and high doses reliably inhibiting self-administration of drugs of abuse. Importantly, self-administration of cocaine, ethanol, and nicotine, but not food, was reduced by MTEP and MPEP in the dose range of 1 to 2mg/kg and 2.5 to 3.2mg/kg, respectively. This dose range corresponds to approximately 50% to 80% mGluR5 occupancy. Interestingly, the limited data found in mice and monkeys showed a similar therapeutic window.. Altogether, this review suggests a therapeutic window for mGluR5 NAMs that can be translated to the treatment of substance-related and addictive disorders.

Topics: Allosteric Regulation; Animals; Cocaine; Drug-Seeking Behavior; Ethanol; Nicotine; Pyridines; Receptor, Metabotropic Glutamate 5; Self Administration; Substance-Related Disorders; Thiazoles

Glutamate regulates the function of central nervous system (CNS), in part, through the cAMP and/or IP3/DAG second messenger-associated metabotropic glutamate receptors (mGluRs). The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) has been extensively used to elucidate potential physiological and pathophysiological functions of mGluR5. Unfortunately, recent evidence indicates significant non-specific actions of MPEP, including inhibition of NMDA receptors. In contrast, in vivo and in vitro characterization of the newer mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) indicates that it is more highly selective for mGluR5 over mGluR1, has no effect on other mGluR subtypes, and has fewer off-target effects than MPEP. This article reviews literature on both of these mGluR5 antagonists, which suggests their possible utility in neurodegeneration, addiction, anxiety and pain management.

Topics: Animals; Humans; Neurodegenerative Diseases; Pain; Pyridines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Substance-Related Disorders; Thiazoles

One of most formidable problems in the treatment of addiction is the high rate of relapse. The discovery of medicines to help mitigate relapse are aided by animal models that currently involve weeks of training and require surgical preparations and drug delivery devices. The present set of experiments was initiated to investigate a rapid 8-day screening method that utilizes food instead of intravenous drug administration. Male Sprague-Dawley rats were trained in a reinstatement paradigm in which every lever press produced a 45 mg food pellet concurrently paired with a light and tone. Behavior was subsequently extinguished with lever responses producing neither food nor food-associated stimuli. Reinstatement of responding was evaluated under conditions in which the first three responses of every 5 min time bin produced a food pellet along with food-associated stimuli. The mGlu

Topics: Amino Acids; Animals; Behavior, Addictive; Behavior, Animal; Bridged Bicyclo Compounds, Heterocyclic; Cannabinoid Receptor Antagonists; Conditioning, Operant; Drug Discovery; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Extinction, Psychological; Feeding Behavior; Male; Models, Animal; Pyridines; Rats; Rats, Sprague-Dawley; Recurrence; Rimonabant; Self Administration; Substance-Related Disorders; Thiazoles

We have recently reported that the metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates acquisition of conditioned place preference (CPP) induced by heroin and ketamine. The present study investigated to what extent this effect of MPEP can be generalized to other classes of drugs, such as the stimulants nicotine and cocaine, and to drugs that produce CPP in the rat despite a lack of abuse potential in humans, such as buspirone and clonidine. Adult male Sprague Dawley rats were subjected to a standard unbiased CPP protocol (six conditioning sessions lasting 20 minutes for nicotine and 40 minutes for the other compounds). Rats were conditioned with either nicotine (0.05-0.2 mg/kg, subcutaneously), cocaine [1-10 mg/kg, intraperitoneally (i.p.)], buspirone (0.3-3 mg/kg, i.p.) or clonidine (0.2-0.6 mg/kg, i.p.) in combination with MPEP (0 or 10 mg/kg, i.p.). For nicotine and cocaine, the minimal effective dose to induce CPP was lowered by pre-treatment with MPEP. While buspirone and clonidine did not induce CPP when given alone (i.e. combined with MPEP vehicle), both compounds induced CPP after pre-treatment with MPEP. It is concluded that MPEP consistently potentiates acquisition of drug-induced reward, independent of the mechanism of action of the co-administered drug. We suggest that the proposed anti-abuse effect of MPEP may be due to a substitution-like effect.

Topics: Animals; Brain; Buspirone; Choice Behavior; Clonidine; Cocaine; Conditioning, Classical; Dose-Response Relationship, Drug; Drug Synergism; Illicit Drugs; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Nicotine; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Social Environment; Substance-Related Disorders

A series of heterobiaryl amides was designed and synthesized as novel mGluR5 antagonists. The synthesis using palladium catalyzed Suzuki-Miyaura cross-coupling reactions provided an array of compounds with a range of in vitro activities. In particular, compound 9e, 4(3,5-difluorophenyl)-N-(6-methylpyridin-1-yl)picolinamide, exhibited nanomolar affinity at the mGluR5 and will serve as a template for future drug design.

Topics: Amides; Animals; Binding Sites; Chemistry, Pharmaceutical; CHO Cells; Cricetinae; Cricetulus; Drug Design; Mice; Models, Chemical; Models, Molecular; Molecular Conformation; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Structure-Activity Relationship; Substance-Related Disorders

Previous studies in metabotropic glutamate 5 receptor (mGlu5 receptor) deficient mice have indicated the importance of this receptor in the self-administration of cocaine and locomotor sensitisation to this stimulant. Both ionotropic and metabotropic receptors have been implicated in drug-seeking and drug-taking behaviours, but the specific role of each subtype of metabotropic glutamate receptors (mGlu receptors) is still unknown. In the present series of experiments we further investigated the role of mGlu5 receptors on nicotine, cocaine- and food-taking behaviour. We also investigated the effects of the mGlu5 receptor antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) on the acute locomotor activating effects of nicotine, the expression of sensitisation to its repeated, intermittent administration, and nicotine-triggered relapse to nicotine-seeking behaviour. The results indicate that MPEP treatment reduced nicotine-induced drug-seeking behaviour in a model of nicotine-triggered relapse to nicotine seeking. Furthermore, MPEP decreased both nicotine and cocaine self-administration without affecting food self-administration under similar schedules of reinforcement. Finally, MPEP reduced both the acute locomotor stimulant effects of nicotine as well as the expression of behavioural sensitisation to its repeated administration. Although the intravenous administration of MPEP at 1 and 10 mg/kg transiently reduced spontaneous locomotor activity during the first 25 min post-administration, we also demonstrated that performance on the accelerating rotarod was not affected when MPEP was given 5 and 30 min prior to the test. Altogether, the present findings strengthen the hypothesis that selective antagonism at mGlu5 receptors may be a new potential pharmacotherapeutic approach for the treatment of drug dependence and addiction.

Topics: Animals; Behavior, Animal; Cocaine; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Injections, Intravenous; Male; Motor Activity; Nicotine; Psychomotor Performance; Pyridines; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Secondary Prevention; Self Administration; Substance-Related Disorders