Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations of striatal synaptic transmission have been associated with several motor disorders involving the basal ganglia, such as Parkinson's disease. For this reason, we investigated the role of group-III metabotropic glutamate (mGlu) receptors in regulating synaptic transmission in the striatum by electrophysiological recordings and by using our novel orthosteric agonist (3S)-3-[(3-amino-3-carboxypropyl(hydroxy)phosphinyl)-hydroxymethyl]-5-nitrothiophene (LSP1-3081) and l-2-amino-4-phosphonobutanoate (L-AP4). Here, we show that both drugs dose-dependently reduced glutamate- and GABA-mediated post-synaptic potentials, and increased the paired-pulse ratio. Moreover, they decreased the frequency, but not the amplitude, of glutamate and GABA spontaneous and miniature post-synaptic currents. Their inhibitory effect was abolished by (RS)-alpha-cyclopropyl-4-phosphonophenylglycine and was lost in slices from mGlu4 knock-out mice. Furthermore, (S)-3,4-dicarboxyphenylglycine did not affect glutamate and GABA transmission. Finally, intrastriatal LSP1-3081 or L-AP4 injection improved akinesia measured by the cylinder test. These results demonstrate that mGlu4 receptor selectively modulates striatal glutamate and GABA synaptic transmission, suggesting that it could represent an interesting target for selective pharmacological intervention in movement disorders involving basal ganglia circuitry.
 ...
PMID:Metabotropic glutamate receptor subtype 4 selectively modulates both glutamate and GABA transmission in the striatum: implications for Parkinson's disease treatment. 1951 81

Group-III metabotropic glutamate receptors (mGluRs) comprise four structurally related brain and retinal G protein-coupled receptors (GPCRs), mGluR4, mGluR6, mGluR7 and mGluR8, which receive much attention as promising targets for nervous system drugs. In particular, activation of mGluR4 is a major focus for the development of new therapeutics in Parkinson's disease, while mGluR7 activation is considered a potential approach for future treatments of specific psychiatric conditions. The first generation group-III mGluR agonists, e.g.l-AP4 and l-SOP, are characterized by an essential phosphonate functional group, which became a major limitation for the development of systemically active, potent and receptor subtype-selective drugs. Recently however, two approaches emerged in parallel providing resolution to this constraint: in silico high-throughput screening of chemical libraries against a 3D-model of the mGluR4 extracellular domain identified a hit that was optimized into a series of potent and subtype-selective orthosteric agonists with drug-like properties and novel chemotype structures; secondly, high-throughput random screening of chemical libraries against recombinantly expressed group-III receptors identified diverse chemical sets of allosteric agonists and positive modulators, which are drug-like, display selectivity for mGluR4, mGluR7, or mGluR8 and act via novel pharmacological sites. Here, we illustrate new scientific insights obtained via the use of those strategies. Also, we compare advantages and disadvantages of both approaches to identify the desired group-III mGluR activators and we conclude with suggestions how to employ those discovery strategies with success for the identification, optimization, and development of clinical drug candidates; this may have important implications for the entire field of GPCR research.
 ...
PMID:Orthosteric versus allosteric GPCR activation: the great challenge of group-III mGluRs. 2255 64


<< Previous 1 2