A double effect molecular switch leads to a novel potent negative allosteric modulator of metabotropic glutamate receptor 5

被引：10
|
作者：
Gomez-Santacana, X. [1 ,2 ,3 ,4 ]
Rovira, X. [2 ,3 ,5 ,6 ]
Dalton, J. A. [2 ,3 ]
Goudet, C. [5 ,6 ]
Pin, J. P. [5 ,6 ]
Gorostiza, P. [4 ,7 ,8 ]
Giraldo, J. [2 ,3 ]
Llebaria, A. [1 ]
机构：
[1] Inst Adv Chem Catalonia IQAC CSIC, Med Chem Lab, Barcelona 08034, Spain
[2] Univ Autonoma Barcelona, Inst Neurociencies, Lab Mol Neuropharmacol & Bioinformat, Bellaterra 08193, Spain
[3] Univ Autonoma Barcelona, Unitat Bioestadist, Bellaterra 08193, Spain
[4] Inst Bioengn Catalonia IBEC, Barcelona 08028, Spain
[5] Univ Montpellier, UMR 5203, CNRS, Inst Genom Fonct, F-34000 Montpellier, France
[6] INSERM, U661, F-34000 Montpellier, France
[7] Network Biomed Res Ctr Bioengn Biomat & Nanomed C, Barcelona, Spain
[8] Catalan Inst Res & Adv Studies ICREA, Barcelona, Spain
来源：
MEDCHEMCOMM | 2014年 / 5卷 / 10期
关键词：
GROUP-III; RAT; ACTIVATION; DISCOVERY; EFFICACY; PROGRESS; LIGANDS; SERIES;
D O I：
10.1039/c4md00208c
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Compounds that modulate the function of G-protein-coupled receptors (GPCRs) by binding to their allosteric sites are of potential interest for the treatment of multiple CNS and non-CNS disorders. Allosteric ligands can act either as positive (PAM), negative (NAM), or silent (SAM) receptor modulators and have numerous advantages over classic orthosteric compounds, including improved GPCR-subtype selectivity: the capacity to adapt to physiological conditions; and better safety profiles. Despite these benefits, allosteric modulators are difficult to design and optimize and are often prone to "molecular switching": a structural phenomenon by which very subtle chemical variations in the ligand result in unexpected changes in selectivity profiles or pharmacology, changing PAMs to NAMs or vice versa. Here, we report the discovery of a nanomolar and subtype selective NAM of metabotropic glutamate receptor 5 (mGlu(5)) through a targeted "double effect molecular switch" of a potent mGlu(4) PAM, and suggests a promising approach towards the discovery of novel mGluR allosteric modulators.
引用
收藏
页码：1548 / 1554
页数：7
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