8-(3-chlorostyryl)caffeine and Parkinson-Disease

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Binding Sites; Calcium Channel Blockers; Chelating Agents; Cholinesterase Inhibitors; Humans; Huntington Disease; Ligands; Multiple Sclerosis; Neurodegenerative Diseases; Neurofibrillary Tangles; Neurotransmitter Agents; Parkinson Disease; Plaque, Amyloid

Modulation of multiple biological targets with a single drug can lead to synergistic therapeutic effects and has been demonstrated to be essential for efficient treatment of CNS disorders. However, rational design of compounds that interact with several targets is very challenging. Here, we demonstrate that structure-based virtual screening can guide the discovery of multi-target ligands of unrelated proteins relevant for Parkinson's disease. A library with 5.4 million molecules was docked to crystal structures of the A

Topics: Adenosine A2 Receptor Antagonists; Animals; Antiparkinson Agents; Binding Sites; Cell Line; Cell Survival; CHO Cells; Cricetulus; Cyclic AMP; Drug Evaluation, Preclinical; Humans; Ligands; Molecular Docking Simulation; Molecular Targeted Therapy; Monoamine Oxidase; Parkinson Disease; Receptor, Adenosine A2A; Structure-Activity Relationship

Monoamine oxidase B (MAO-B) plays a key role in the metabolism of dopamine, a neurotransmitter critical for the maintenance of cognitive function. Consequently, MAO-B is an important therapeutic target for disorders characterized by a decline in dopaminergic neurotransmission, including Parkinson's disease (PD). An emerging strategy in drug discovery is to utilize the biophysical approaches of thermal shift and isothermal titration calorimetry (ITC) to gain insight into binding modality and identify thermodynamically privileged chemical scaffolds. Described here is the development of such approaches for reversible and irreversible small molecule inhibitors of MAO-B. Investigation of soluble recombinant MAO-B revealed mechanism-based differences in the thermal shift and binding thermodynamic profiles of MAO-B inhibitors. Irreversible inhibitors demonstrated biphasic protein melt curves, large enthalpically favorable and entropically unfavorable binding, in contrast to reversible compounds, which were characterized by a dose-dependent increase in thermal stability and enthalpically-driven binding. The biophysical approaches described here aim to facilitate the discovery of next-generation MAO-B inhibitors.

Topics: Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Small Molecule Libraries; Thermodynamics

The present work showed the effects of 8-(-3-chlorostyryl)-caffeine (CSC), an A(2A) receptors antagonist and MAO B inhibitor, on behavior and biochemical alterations in 6-OHDA-lesioned rats. Male Wistar rats (280 g) were injected with CSC (1 and 5 mg/kg, i.p.) alone or combined with l-DOPA (50 mg/kg+benserazide 12.5 mg/kg), starting 6 days after the striatal 6-OHDA lesions, and once daily for the next 7 days. Fourteen days after the 6-OHDA lesion (and 24 h after CSC or vehicle), the number of net body rotations/h (after the apomorphine challenge) was recorded and, at the next day, animals were sacrificed. The ipsilateral striatum was used for HPLC measurements of monoamines and amino acids or for determination of nitrite contents and lipid peroxidation. Results showed that the increase in body rotation, induced by the 6-OHDA lesion, after the apomorphine challenge, was significantly and dose-dependently reversed by CSC. Furthermore, the decreased striatal levels of DA and metabolites, in the 6-OHDA-lesioned rats, were reversed after CSC treatment, and these effects were potentiated after the combination with l-DOPA. Similar results were observed with NE, 5-HT and 5-HIAA. While glutamate and GABA were increased in the 6-OHDA-lesioned group, CSC alone or mainly combined with l-DOPA reversed these alterations. In addition, the CSC treatment of 6-OHDA-lesioned rats reversed the increased nitrite formation and lipid peroxidation induced by 6-OHDA. In conclusion, CSC by means of its dual action as A(2A) antagonist and MAO-B inhibitor reversed behavior and biochemical alterations, observed in the 6-OHDA-lesioned rats, pointing out to its potential benefit for the treatment of PD.

Topics: Adenosine A2 Receptor Agonists; Animals; Behavior, Animal; Biogenic Monoamines; Caffeine; Disease Models, Animal; Dose-Response Relationship, Drug; Hydroxyindoleacetic Acid; Lipid Peroxidation; Male; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neostriatum; Neuroprotective Agents; Nitrites; Norepinephrine; Oxidopamine; Parkinson Disease; Rats; Rats, Wistar; Receptors, Adenosine A2; Rotation; Serotonin