Metabotropic glutamate receptors as therapeutic targets in Parkinson's disease: An update from the last 5 years of research.
Identifieur interne : 000065 ( Main/Exploration ); précédent : 000064; suivant : 000066Metabotropic glutamate receptors as therapeutic targets in Parkinson's disease: An update from the last 5 years of research.
Auteurs : Nadhir Litim [Canada] ; Marc Morissette [Canada] ; Thérèse Di Paolo [Canada]Source :
- Neuropharmacology [ 1873-7064 ] ; 2017.
Abstract
Disturbance of glutamate neurotransmission in Parkinson's disease (PD) and l-DOPA induced dyskinesia (LID) is well documented. This review focuses on advances during the past five years on pharmacological modulation of metabotropic glutamate (mGlu) receptors in relation to anti-parkinsonian activity, LID attenuation, and neuroprotection. Drug design and characterization have led to the development of orthosteric agonists binding the same site as glutamate and Positive and Negative Allosteric modulators (PAMs and NAMs) binding sites different from the orthosteric site and offering subtype selectivity. Inhibition of group I (mGlu1 and mGlu5) receptors with NAMs and activation of group II (mGlu2 and 3 receptors) and group III (mGlu 4, 7 and 8 receptors) with PAMs and orthosteric agonists have shown their potential to inhibit glutamate release and attenuate excitotoxicity. Earlier and recent studies have led to the development of mGlu5 receptors NAMs to reduce LID and for neuroprotection, mGlu3 receptor agonists for neuroprotection while mGlu4 receptor PAMs and agonists for antiparkinsonian effects and neuroprotection. Furthermore, homo- and heterodimers of mGlu receptors are documented and highlight the complexity of the functioning of these receptors. Research on partial allosteric modulators and biased mGlu receptor allosteric modulators offer new glutamatergic drugs with better therapeutic effects and less off target adverse activity. Thus these various mGlu receptor targets will enable the development of novel drugs with improved clinical effects for normalization of glutamate transmission, treat PD and LID relief. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.
DOI: 10.1016/j.neuropharm.2016.03.036
PubMed: 27055772
Affiliations:
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Electronic address: Therese.Dipaolo@crchul.ulaval.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, Canada; Faculty of Pharmacy, Laval University, Quebec City</wicri:regionArea><wicri:noRegion>Quebec City</wicri:noRegion></affiliation></author></analytic><series><title level="j">Neuropharmacology</title><idno type="eISSN">1873-7064</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Disturbance of glutamate neurotransmission in Parkinson's disease (PD) and l-DOPA induced dyskinesia (LID) is well documented. This review focuses on advances during the past five years on pharmacological modulation of metabotropic glutamate (mGlu) receptors in relation to anti-parkinsonian activity, LID attenuation, and neuroprotection. Drug design and characterization have led to the development of orthosteric agonists binding the same site as glutamate and Positive and Negative Allosteric modulators (PAMs and NAMs) binding sites different from the orthosteric site and offering subtype selectivity. Inhibition of group I (mGlu1 and mGlu5) receptors with NAMs and activation of group II (mGlu2 and 3 receptors) and group III (mGlu 4, 7 and 8 receptors) with PAMs and orthosteric agonists have shown their potential to inhibit glutamate release and attenuate excitotoxicity. Earlier and recent studies have led to the development of mGlu5 receptors NAMs to reduce LID and for neuroprotection, mGlu3 receptor agonists for neuroprotection while mGlu4 receptor PAMs and agonists for antiparkinsonian effects and neuroprotection. Furthermore, homo- and heterodimers of mGlu receptors are documented and highlight the complexity of the functioning of these receptors. Research on partial allosteric modulators and biased mGlu receptor allosteric modulators offer new glutamatergic drugs with better therapeutic effects and less off target adverse activity. Thus these various mGlu receptor targets will enable the development of novel drugs with improved clinical effects for normalization of glutamate transmission, treat PD and LID relief. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Litim, Nadhir" sort="Litim, Nadhir" uniqKey="Litim N" first="Nadhir" last="Litim">Nadhir Litim</name></noRegion><name sortKey="Di Paolo, Therese" sort="Di Paolo, Therese" uniqKey="Di Paolo T" first="Thérèse" last="Di Paolo">Thérèse Di Paolo</name><name sortKey="Morissette, Marc" sort="Morissette, Marc" uniqKey="Morissette M" first="Marc" last="Morissette">Marc Morissette</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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