The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2

D'Alessandro, Pier Luca; Corti, Corrado; Roth, Adelheid; Ugolini, Annarosa; Sava, Anna; Montanari, Dino; Bianchi, Federica; Garland, Stephen L.; Powney, Ben; Koppe, Emma; Rocheville, Magalie; Osborne, Greg; Pérez, Paloma; Fuente, Jesús de la; Frailes, Maite de los; Smith, Paul W.; Branch, Clive L.; Nash, David J.; Watson, Steve P.

doi:10.1016/j.bmcl.2009.11.032

Cited by 21 publications

(22 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although several novel types of positive allosteric modulators have been discovered (XII-XVI in Table 8) (Zhang et al, 2008b;Duplantier et al, 2009;Brnardic et al, 2010;Cid et al, 2010;D'Alessandro et al, 2010;Tresadern et al, 2010), only few negative allosteric modulators of group II mGlu receptors are known. For two non-amino acid-based classes of group II antagonists Wichmann et al, 1999), it has not been clearly established whether they are competitive or allosteric.…”

Section: Allosteric Modulation Of Family C Gpcrsmentioning

confidence: 99%

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

2011

View full text Add to dashboard Cite

Section: Allosteric Modulation Of Family C Gpcrsmentioning

confidence: 99%

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

2011

View full text Add to dashboard Cite

“…In addition, as far as we are aware there have been no studies documenting the effects of modifying the cyclopentyl ring in this scaffold. Furthermore, despite several recent reports disclosing mGluR2 PAMs,11,15 none have been evaluated in an in vivo model of drug dependence.…”

mentioning

confidence: 99%

Design and Synthesis of an Orally Active Metabotropic Glutamate Receptor Subtype-2 (mGluR2) Positive Allosteric Modulator (PAM) That Decreases Cocaine Self-Administration in Rats

Dhanya

Sidique

Sheffler³

et al. 2010

J. Med. Chem.

View full text Add to dashboard Cite

The modification of 3′-((2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yloxy)methyl)biphenyl-4-carboxylic acid (BINA, 1) by incorporating heteroatoms into the structure and replacing the cyclopentyl moiety led to the development of new mGluR2 positive allosteric modulators (PAMs) with optimized potency and superior drug-like properties. These analogues are more potent than 1 in vitro, and are highly selective for mGluR2 vs. other mGluR subtypes. They have significantly improved pharmacokinetic (PK) properties, with excellent oral bioavailability and brain penetration. The benzisothiazol-3-one derivative 14 decreased cocaine self-administration in rats, providing proof-of-concept for the use of mGluR2 PAMs for the treatment of cocaine dependence. KeywordsMetabotropic glutamate receptors; agonist; positive allosteric modulators; BINA; cocaine selfadministration Cocaine addiction is a chronic relapsing disorder affecting more than 1.6 million Americans. 1 Relapse rates among cocaine users is in the range of 94-99%, the highest among all commonly abused drugs. 2 Chronic cocaine abuse can lead to severe neurotoxicity, psychosis, lethargy, depression, or potentially death through a fatal overdose. Currently there is no effective treatment for cocaine dependence, and therefore cocaine addiction constitutes a major public health problem. Consequently, there is a significant need to identify new therapeutic agents for the treatment of cocaine and other psychomotor stimulant addictions. Recent findings suggest that neuroadaptations in glutamatergic * Corresponding Author: To whom correspondence should be addressed. ncosford@sanfordburnham.org. † These authors contributed equally to this work. NIH Public AccessAuthor Manuscript J Med Chem. Author manuscript; available in PMC 2012 January 13. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript transmission produced by repeated exposure to cocaine or other drugs of abuse are likely to contribute to the maintenance of addictive behaviors including drug use, craving and relapse to drug taking in humans. 3 Specifically, it has been shown that repeated cocaine exposure alters the function of Group II metabotropic glutamate receptors (mGluRs). 4a The Group II mGluRs include the mGluR2 and mGluR3 subtypes, which couple to G i/o proteins to negatively regulate the activity of adenylyl cyclase. 4b Brain regions implicated in different aspects of drug abuse and drug dependence, including the cerebral cortex, hippocampus, striatum, amygdala, frontal cortex and nucleus accumbens display high levels of mGluR2 and mGluR3 binding, 5 suggesting a role for the mGluR2/3 subtypes in the development of cocaine dependence and as potential targets for therapeutic agents. 3a,3e,3f,6 Orthosteric (glutamate site) mGluR2/3 agonists such as LY379268 6g are constrained amino acid analogues that do not exhibit selectivity for mGluR2 versus mGluR3, presumably because of the high degree of sequence homology at the glutamate binding site for these two recept...

show abstract

“…Compounds are claimed to have FLIPR EC 50 activities lower than 10 μM, with preferred examples having activities lower than 1 μM in both FLIPR and GTPγS assays. Detailed SAR has been reported in a subsequent publication [58] describing the optimization process from the HTS hit 65, focusing on improving potency as well as reducing clearance. The explorations carried out at both N and C 5 positions converged on the identification of 66, a compound with improved potency and PK.…”

Section: Cyclic Carbamatesmentioning

confidence: 99%

“…[38] Since the discovery of LY487379 and BINA and up to early 2009, a variety of structurally diverse chemotypes were published in both patent applications and research journals. Thus, shortly after the publication of LY487379, series such as acetophenones [44][45][46][47], indoles [48], 1,5-pyridones [49], 1,4-pyridones [50], isoindolones [51,52], pyrazolones [53], thienopyrimidines [54], oxazolidinones [55,56], benzimidazoles [57][58][59] and oxazolopyrimidones [60], were reported as novel mGlu2 receptor PAM chemotypes. For detailed background information, we refer to the reviews by Sheffler [61], Rudd and McCauley [62], Fraley [63], Marek [64] and Trabanco [65,66], which cover literature and patent applications.…”

Section: Mglu2 Receptor Positive Allosteric Modulatorsmentioning

confidence: 99%

See 1 more Smart Citation

Metabotropic Glutamate Receptor 2 Activators

Cid¹,

Trabanco²,

Lavreysen

2014

Small Molecule Therapeutics for Schizophrenia

View full text Add to dashboard Cite

Schizophrenia is a common and severe, often disabling psychiatric illness of unknown aetiology that affects approximately 24 million people worldwide. The illness is characterized by symptomatology comprising positive symptoms (hallucinations and delusional behaviours), negative symptoms (anhedonia, social withdrawal and apathy) and cognitive dysfunction (diminished capacity for learning, memory and executive function). Current pharmacological treatments are effective at alleviating positive symptoms but have limited impact on negative symptoms and cognitive deficits. Furthermore, the extrapyramidal symptoms, hyperprolactinemia and metabolic syndrome, including substantial weight gain, are typical side effects limiting the value of many of these drugs for patients. Thus, drugs that better serve the patient population by effectively treating all symptoms with improved safety and tolerability remain a critical unmet need. Modulation of the metabotropic glutamate type 2 (mGlu2) receptor has emerged as a promising mechanism for the treatment of CNS diseases, with the potential to provide a new and more effective avenue for the treatment of schizophrenia.

show abstract

The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2

Cited by 21 publications

References 19 publications

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Design and Synthesis of an Orally Active Metabotropic Glutamate Receptor Subtype-2 (mGluR2) Positive Allosteric Modulator (PAM) That Decreases Cocaine Self-Administration in Rats

Metabotropic Glutamate Receptor 2 Activators

Contact Info

Product

Resources

About