Development of allosteric modulators of GPCRs for treatment of CNS disorders

被引：176

作者：

Nickols, Hilary Highfield ^{[1
]}

Conn, P. Jeffrey ^{[2
]}

机构：

[1] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Div Neuropathol, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA

来源：

NEUROBIOLOGY OF DISEASE | 2014年 / 61卷

关键词：

Allosteric modulator; CNS; Drug discovery; GPCR; Metabotropic glutamate receptor; Muscarinic acetylcholine receptor; METABOTROPIC GLUTAMATE-RECEPTOR; MUSCARINIC ACETYLCHOLINE-RECEPTOR; METHYL-D-ASPARTATE; DOPA-INDUCED DYSKINESIA; FRAGILE-X-SYNDROME; PROTEIN-COUPLED RECEPTORS; CENTRAL-NERVOUS-SYSTEM; TRANSMEMBRANE SPANNING RECEPTORS; PARKINSONS-DISEASE TREATMENT; PREPULSE INHIBITION DEFICIT;

D O I：

10.1016/j.nbd.2013.09.013

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as "bitopic" ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.

引用

页码：55 / 71

页数：17

共 320 条

[11]

Awad H, 2000, J NEUROSCI, V20, P7871

[12] mGluR5 Positive Allosteric Modulators Facilitate both Hippocampal LTP and LTD and Enhance Spatial Learning [J].

Ayala, Jennifer E. ;

Chen, Yelin ;

Banko, Jessica L. ;

Sheffler, Douglas J. ;

Williams, Richard ;

Telk, Alexandra N. ;

Watson, Noreen L. ;

Xiang, Zixiu ;

Zhang, Yongqin ;

Jones, Paulianda J. ;

Lindsley, Craig W. ;

Olive, M. Foster ;

Conn, P. Jeffrey .

NEUROPSYCHOPHARMACOLOGY, 2009, 34 (09) :2057-2071

[13] THE CHOLINERGIC HYPOTHESIS OF GERIATRIC MEMORY DYSFUNCTION [J].

BARTUS, RT ;

DEAN, RL ;

BEER, B ;

LIPPA, AS .

SCIENCE, 1982, 217 (4558) :408-417

[14] Pharmacological activation of mGlu4 metabotropic glutamate receptors reduces nigrostriatal degeneration in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [J].

Battaglia, Giuseppe ;

Busceti, Carla L. ;

Molinaro, Gemma ;

Biagioni, Francesca ;

Traficante, Anna ;

Nicoletti, Ferdinando ;

Bruno, Valeria .

JOURNAL OF NEUROSCIENCE, 2006, 26 (27) :7222-7229

[15] The mGIuR theory of fragile X mental retardation [J].

Bear, MF ;

Huber, KM ;

Warren, ST .

TRENDS IN NEUROSCIENCES, 2004, 27 (07) :370-377

[16] Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests [J].

Belozertseva, I. V. ;

Kos, T. ;

Popik, P. ;

Danysz, W. ;

Bespalov, A. Y. .

EUROPEAN NEUROPSYCHOPHARMACOLOGY, 2007, 17 (03) :172-179

[17] Fused tricyclic mGluR1 antagonists for the treatment of neuropathic pain [J].

Bennett, Chad E. ;

Burnett, Duane A. ;

Greenlee, William J. ;

Knutson, Chad E. ;

Korakas, Peter ;

Li, Cheng ;

Tulshian, Deen ;

Wu, Wen-Lian ;

Bertorelli, Rosalia ;

Fredduzzi, Silva ;

Grilli, Mariagrazia ;

Lozza, Gianluca ;

Reggiani, Angelo ;

Veltri, Alessio .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (04) :1575-1578

[18] A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis [J].

Benneyworth, Michael A. ;

Xiang, Zixiu ;

Smith, Randy L. ;

Garcia, Efrain E. ;

Conn, P. Jeffrey ;

Sanders-Bush, Elaine .

MOLECULAR PHARMACOLOGY, 2007, 72 (02) :477-484

[19] Synergy between L-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: Implications for Parkinson's disease treatment and dyskinesia [J].

Bennouar, Khaled-Ezaheir ;

Uberti, Michelle A. ;

Melon, Christophe ;

Bacolod, Maria D. ;

Jimenez, Hermogenes N. ;

Cajina, Manuel ;

Goff, Lydia Kerkerian-Le ;

Doller, Dario ;

Gubellini, Paolo .

NEUROPHARMACOLOGY, 2013, 66 :158-169

[20] The muscarinic receptor antagonist tropicamide suppresses tremulous jaw movements in a rodent model of parkinsonian tremor: possible role of M4 receptors [J].

Betz, Adrienne J. ;

McLaughlin, Peter J. ;

Burgos, Melissa ;

Weber, Suzanne M. ;

Salamone, John D. .

PSYCHOPHARMACOLOGY, 2007, 194 (03) :347-359

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