Parkinson disease structure

Trimethyl-1,4-naphthoquinone (TMNQ) is a quinone that was recently isolated from tobacco leaves and was shown to slow the metabolism of dopamine, a neurotransmitter whose depletion can lead to Parkinsons disease. What is the structure of the hydroquinone whose oxidation gives TMNQ ... 

In addition, Pfizer has identified a number of related, fused bicyclic pyrazole analogues [286-292]. These compounds, of which structures (419 25) are specified examples, are claimed to be of use in the treatment of a number of diseases including alcoholism, psychosis, tobacco abuse, Parkinson s disease and obesity. 

Furthermore, the presence of CB1 in the structures and pathways associated with the pathophysiology of Tourette s syndrome, and especially the functional link between CB1 and Di, D2, also argues that the endocannabinoid system may have some involvement in this disorder as well (Consroe, 1998). In addition, it has been suggested that activation of CB1 receptors, also owing to their link with the dopaminergic system, may reduce dyskinesia produced by L-DOPA in patients with Parkinson s disease (Brotsie, 1998). 

Basal ganglia A group of networked structures in the brain which control voluntary movement. Two basal ganglia disorders are Huntington s disease and Parkinson s disease. 

The 140-residue protein AS is able to form amyloid fibrils and as such is the main component of protein inclusions involved in Parkinson s disease. Full-length 13C/15N-labelled AS fibrils and AS reverse-labelled for two of the most abundant amino acids, K and V, were examined by homonuclear and heteronuclear 2D and 3D NMR.147 Two different types of fibrils display chemical shift differences of up to 13 ppm in the l5N dimension and up to 5 ppm for the backbone and side-chain 13C chemical shifts. Selection of regions with different mobility indicates the existence of monomers in the sample and allows the identification of mobile segments of the protein within the fibril in the presence of monomeric protein. At least 35 C-terminal residues are mobile and lack a defined secondary structure, whereas the N terminus is rigid starting from residue 22. In addition, temperature-dependent sensitivity enhancement is also noted for the AS fibrils due to both the CP efficiency and motional interference with proton decoupling.148... 

Glial cytoplasmic inclusions are strongly immunoreac-tive for a-synuclein and filaments isolated from the brains of patients with multiple system atrophy are labeled by a-synuclein antibodies [10]. As in dementia with Lewy bodies, assembled a-synuclein is nitrated and phosphory-lated at S129, and the number of a-synuclein-positive structures exceeds that stained by anti-ubiquitin antibodies, confirming that the accumulation of a-synuclein precedes ubiquitination. Filament morphologies and their staining characteristics were found to be similar to those of filaments extracted from the brains of patients with Parkinson s disease and dementia with Lewy bodies. 

Dystonia due to identifiable structural or biochemical abnormalities ( secondary dystonia) often occurs weeks or months after strokes or other focal lesions, which commonly involve the basal ganglia, but may also involve the thalamus or cerebellum. Dystonia is also seen in children with cerebral palsy and in patients with abnormalities of dopaminergic transmission. For instance, dystonia may develop in the context of Parkinson s disease, either as an early parkinsonian sign, or in response to dopaminergic drugs. A particularly interesting inherited disease results in a combination of dystonia and parkinsonian features at a young age, which responds dramatically to treatment with low-dose levodopa ( dopamine-responsive dystonia ). 

Tropane derivative tesofensine, also known as NS2330 (28), is reported to be a triple reuptake inhibitor. Its efficacy as a monotherapy in early Parkinson s disease was evaluated in a clinical trial however, it did not provide significantly greater benefits than placebo [90]. NS2330 is also reported to be in clinical trials for obesity [68]. NS2359 (GSK 372475, structure not disclosed), also a triple reuptake inhibitor, is reportedly in clinical development for depression and ADHD, as well as addictive disorders [68]. 

Various drugs used in the treatment of Parkinson s disease (e.g., Benactyzine) can be hallucinogenic at higher doses. However, since they seem to produce a trip like that of the glycolate esters (Ditran, etc.), which they structurally resemble, these compounds should be avoided. 

Lashuel, H. A., Petre, B. M., Wall, J., Simon, M., Nowak, R. J., Walz, T., and Lansbury, P. T., Jr. (2002). Alpha-synuclein, especially the Parkinson s disease-associated mutants, forms pore-like annular and tubular protofibrils./. Mol. Biol. 322,1089-1102. LeVine, H. (1993). Thioflavine T interaction with synthetic Alzheimer s disease beta-amyloid peptides Detection of amyloid aggregation in solution. Protein Sci. 2, 404—410. Lin, H., Bhatia, R., and Lai, R. (2001). Amyloid beta protein forms ion channels Implications for Alzheimer s disease pathophysiology. FASEB J. 15, 2433-2444. Lorenzo, A., and Yankner, B. A. (1994). Beta-amyloid neurotoxicity requires fibril formation and is inhibited by Congo red. Proc. Natl. Acad. Sci. USA 91, 12243-12247. Luhrs, T., Ritter, C., Adrian, M., Riek-Loher, D., Bohrmann, B., Dobeli, H., Schubert, D., and Riek, R. (2005). 3D structure of Alzheimer s amyl o id-( be la) (1—12) fibrils. Proc. Natl. Acad. Sci. USA 102, 17342-17347. 

---