18 research outputs found
The Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator ADX88178 Inhibits Inflammatory Responses in Primary Microglia
Discovery, Synthesis, and StructureâActivity Relationship Development of a Series of <i>N</i>-4-(2,5-Dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): Characterization of a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu<sub>4</sub>) with Oral Efficacy in an Antiparkinsonian Animal Model
There is an increasing amount of literature data showing
the positive
effects on preclinical antiparkinsonian rodent models with selective
positive allosteric modulators of metabotropic glutamate receptor
4 (mGlu<sub>4</sub>). However, most of the data generated utilize
compounds that have not been optimized for druglike properties, and
as a consequence, they exhibit poor pharmacokinetic properties and
thus do not cross the bloodâbrain barrier. Herein, we report
on a series of <i>N</i>-4-(2,5-dioxopyrrolidin-1-yl)Âphenylpicolinamides
with improved PK properties with excellent potency and selectivity
as well as improved brain exposure in rodents. Finally, ML182 was
shown to be orally active in the haloperidol induced catalepsy model,
a well-established antiparkinsonian model
Discovery, Synthesis, and StructureâActivity Relationship Development of a Series of N
Comparison of Mono-dopaminergic and Multi-target Pharmacotherapies in Primary Parkinson Syndrome and Assessment Tools to Evaluate Motor and Non-motor Symptoms
Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys
Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinsonâs disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinsonâs disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2â0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinsonâs disease
Protective Agents in Parkinson's Disease: Caffeine and Adenosine A2A Receptor Antagonists
The pharmacologic management of Parkinsonâs disease is based on drugs that act on the motor symptoms, whereas there are currently no drugs available that can alter the progressive neurodegeneration of dopaminergic neurons. Based on recent findings suggesting that the adenosinergic system is one of the most interesting in the field of neuroprotection in Parkinsonâs disease, this chapter describes the functions of adenosine and its receptors in the central nervous system, with particular emphasis on their role in neurotoxicity/neuroprotection. Results of epidemiologic surveys demonstrating that intake of caffeine, an adenosine A1/A2A receptor antagonist, is inversely correlated with Parkinsonâs disease are summarized. Moreover, evidence originating from preclinical studies showing that the antagonism of the adenosine A2A receptor is responsible for the neuroprotective effects of caffeine is also presented. This chapter therefore provides a comprehensive analysis of the current literature concerning the adenosinergic-based neuroprotective intervention strategy for Parkinsonâs disease
Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis
Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory.
Astrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known. We found that humans with Alzheimer's disease (AD) had increased levels of the Gs-coupled adenosine receptor A2A in astrocytes. Conditional genetic removal of these receptors enhanced long-term memory in young and aging mice and increased the levels of Arc (also known as Arg3.1), an immediate-early gene that is required for long-term memory. Chemogenetic activation of astrocytic Gs-coupled signaling reduced long-term memory in mice without affecting learning. Like humans with AD, aging mice expressing human amyloid precursor protein (hAPP) showed increased levels of astrocytic A2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss