Allosteric Modulators for mGlu Receptors

The metabotropic glutamate receptor family comprises eight subtypes (mGlu1-8) of G-protein coupled receptors. mGlu receptors have a large extracellular domain which acts as recognition domain for the natural agonist glutamate. In contrast to the ionotropic glutamate receptors which mediate the fast excitatory neurotransmission, mGlu receptors have been shown to play a more modulatory role and have been proposed as alternative targets for pharmacological interventions. The potential use of mGluRs as drug targets for various nervous system pathologies such as anxiety, depression, schizophrenia, pain or Parkinson’s disease has triggered an intense search for subtype selective modulators and resulted in the identification of numerous novel pharmacological agents capable to modulate the receptor activity through an interaction at an allosteric site located in the transmembrane domain. The present review presents the most recent developments in the identification and the characterization of allosteric modulators for the mGlu receptors.     

G-蛋白偶联受体和神经再生

神经再生持续于哺乳动物整个成年期。成年神经再生受多种因素调节,包括神经营养因子、应激、炎性细胞因子以及G-蛋白偶联受体等。大量研究认为,神经再生障碍是抑郁症的发病机制。本文将围绕G-蛋白偶联受体将调控神经再生机制的研究进展进行综述,为以提高神经再生为靶点的抗抑郁药的研发奠定基础。     

Research Strategies for Orphan G-Protein-Coupled Receptors

The Society for Medicines Research meeting on orphan G-protein-coupled receptors (GPCRs) was held on March 7, 2002 at the Novartis Research Centre in Horsham, United Kingdom. The dynamic and highly competitive field of GPCR research was the focus of this SMR meeting, featuring speakers from Pharmagene, Manchester University, GlaxoSmithKline, The Royal Danish School of Pharmacy, Pfizer, AstraZeneca, Merck and Synaptic. The meeting attracted a large and enthusiastic audience interested in the research efforts of leading international research teams in the area of GPCR research, whose immediate aim is to evolve the novel molecular targets into lead discovery programs. (c) 2002 Prous Science. All rights reserved.     

Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

Allosteric modulators of G protein-coupled receptors (GPCRs), which target at allosteric sites, have significant advantages against the corresponding orthosteric compounds including higher selectivity, improved chemical tractability or physicochemical properties, and reduced risk of receptor oversensitization. Bitopic ligands of GPCRs target both orthosteric and allosteric sites. Bitopic ligands can improve binding affinity, enhance subtype selectivity, stabilize receptors, and reduce side effects. Discovering allosteric modulators or bitopic ligands for GPCRs has become an emerging research area, in which the design of allosteric modulators is a key step in the detection of bitopic ligands. Radioligand binding and functional assays ([³⁵S]GTPγS and ERK1/2 phosphorylation) are used to test the effects for potential modulators or bitopic ligands. High-throughput screening (HTS) in combination with disulfide trapping and fragment-based screening are used to aid the discovery of the allosteric modulators or bitopic ligands of GPCRs. When used alone, these methods are costly and can often result in too many potential drug targets, including false positives. Alternatively, low-cost and efficient computational approaches are useful in drug discovery of novel allosteric modulators and bitopic ligands to help refine the number of targets and reduce the false-positive rates. This review summarizes the state-of-the-art computational methods for the discovery of modulators and bitopic ligands. The challenges and opportunities for future drug discovery are also discussed.Key words: allosteric modulators, bitopic ligands, computational approaches, drug discovery, drug target discovery, G protein-coupled receptors     

5-Arylbenzothiadiazine Type Compounds as Positive Allosteric Modulators of AMPA/Kainate Receptors

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Strategic Research Institute G-Protein-Coupled Receptors Drug Discovery World Summit

The Strategic Research Institute provided a well-organised 2-day summit that offered presentations and posters on new assay technology, structure-based small-molecule discovery and examples of clinical candidates targeted to G-protein-coupled receptor (GPCR) targets. A wide variety of topics were presented providing recent advances in GPCR target selection, bioassay-enabling technology and medicinal chemistry targeted to GPCR-relevant chemical libraries. GPCRs continue to be an attractive platform for drug discovery.     

Strategic Research Institute G-Protein-Coupled Receptors Drug Discovery World Summit

The Strategic Research Institute provided a well-organised 2-day summit that offered presentations and posters on new assay technology, structure-based small-molecule discovery and examples of clinical candidates targeted to G-protein-coupled receptor (GPCR) targets. A wide variety of topics were presented providing recent advances in GPCR target selection, bioassay-enabling technology and medicinal chemistry targeted to GPCR-relevant chemical libraries. GPCRs continue to be an attractive platform for drug discovery.     

Allosteric Modulation of Muscarinic Acetylcholine Receptors

Muscarinic acetylcholine receptors (mAChRs) are prototypical Family A G protein coupled-receptors. The five mAChR subtypes are widespread throughout the periphery and the central nervous system and, accordingly, are widely involved in a variety of both physiological and pathophysiological processes. There currently remains an unmet need for better therapeutic agents that can selectively target a given mAChR subtype to the relative exclusion of others. The main reason for the lack of such selective mAChR ligands is the high sequence homology within the acetylcholine-binding site (orthosteric site) across all mAChRs. However, the mAChRs possess at least one, and likely two, extracellular allosteric binding sites that can recognize small molecule allosteric modulators to regulate the binding and function of orthosteric ligands. Extensive studies of prototypical mAChR modulators, such as gallamine and alcuronium, have provided strong pharmacological evidence, and associated structure-activity relationships (SAR), for a “common” allosteric site on all five mAChRs. These studies are also supported by mutagenesis experiments implicating the second extracellular loop and the interface between the third extracellular loop and the top of transmembrane domain 7 as contributing to the common allosteric site. Other studies are also delineating the pharmacology of a second allosteric site, recognized by compounds such as staurosporine. In addition, allosteric agonists, such as McN-A-343, AC-42 and N-desmethylclozapine, have also been identified. Current challenges to the field include the ability to effectively detect and validate allosteric mechanisms, and to quantify allosteric effects on binding affinity and signaling efficacy to inform allosteric modulator SAR.     

Discovery of Naphthyl-Fused 5-Membered Lactams as a New Class of M1 Positive Allosteric Modulators

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Allosteric Binding Site and Activation Mechanism of Class C G-Protein Coupled Receptors: Metabotropic Glutamate Receptor Family

Metabotropic glutamate receptors (mGluR) are mainly expressed in the central nervous system (CNS) and contain eight receptor subtypes, named mGluR1 to mGluR8. The crystal structures of mGluR1 and mGluR5 that are bound with the negative allosteric modulator (NAM) were reported recently. These structures provide a basic model for all class C of G-protein coupled receptors (GPCRs) and may aid in the design of new allosteric modulators for the treatment of CNS disorders. However, these structures are only combined with NAMs in the previous reports. The conformations that are bound with positive allosteric modulator (PAM) or agonist of mGluR1/5 remain unknown. Moreover, the structural information of the other six mGluRs and the comparisons of the mGluRs family have not been explored in terms of their binding pockets, the binding modes of different compounds, and important binding residues. With these crystal structures as the starting point, we built 3D structural models for six mGluRs by using homology modeling and molecular dynamics (MD) simulations. We systematically compared their allosteric binding sites/pockets, the important residues, and the selective residues by using a series of comparable dockings with both the NAM and the PAM. Our results show that several residues played important roles for the receptors’ selectivity. The observations of detailed interactions between compounds and their correspondent receptors are congruent with the specificity and potency of derivatives or compounds bioassayed in vitro. We then carried out 100 ns MD simulations of mGluR5 (residue 26-832, formed by Venus Flytrap domain, a so-called cysteine-rich domain, and 7 trans-membrane domains) bound with antagonist/NAM and with agonist/PAM. Our results show that both the NAM and the PAM seemed stable in class C GPCRs during the MD. However, the movements of “ionic lock,” of trans-membrane domains, and of some activation-related residues in 7 trans-membrane domains of mGluR5 were congruent with the findings in class A GPCRs. Finally, we selected nine representative bound structures to perform 30 ns MD simulations for validating the stabilities of interactions, respectively. All these bound structures kept stable during the MD simulations, indicating that the binding poses in this present work are reasonable. We provided new insight into better understanding of the structural and functional roles of the mGluRs family and facilitated the future structure-based design of novel ligands of mGluRs family with therapeutic potential.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-015-9742-8) contains supplementary material, which is available to authorized users.KEY WORDS: allosteric, class C of G protein-coupled receptors, homology model, metabotropic glutamate receptor family, molecular dynamics simulation     

Discovery of Oxazolobenzimidazoles as Positive Allosteric Modulators for the mGluR2 Receptor

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Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects

Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu₅) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu₅ NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu₅ NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu₅ NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu₅ NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant- and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu₅ NAMs in these assays corresponded with increasing in vivo mGlu₅ occupancy, demonstrating an orderly occupancy-to-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu₅ NAM activity is sufficient to produce therapeutic effects similar to full mGlu₅ NAMs, but with a broader therapeutic index.