Anti-Parkinson activity

Many patents have been issued on the use of pyrogaUol derivatives as pharmaceuticals. PyrogaUol has been used extemaUy in the form of an ointment or a solution in the treatment of skin diseases, eg, psoriasis, ringworm, and lupus erythematosus. GaUamine triethiodide (16) is an important muscle relaxant in surgery it also is used in convulsive-shock therapy. Trimethoprim (2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine) is an antimicrobial and is a component of Bactrin and Septra. Trimetazidine (l(2,3,4-trimethoxybenzyl)piperazine (Vastarel, Yosimilon) is used as a coronary vasodilator. l,2,3,4-Tetrahydro-6-methoxy-l-(3,4,5-trimethoxyphenyl)-9JT-pyrido[3,4- ]indole hydrochloride is useful as a tranquilizer (52) (see Hypnotics, sedatives, ANTICONVULSANTS, AND ANXIOLYTICS). Substituted indanones made from pyrogaUol trimethyl ether depress the central nervous system (CNS) (53). Tyrosine-and glycine(2,3,4-trihydroxybenzyl)hydrazides are characterized by antidepressant and anti-Parkinson activity (54). 

Some other claims made for these quinuclidine derivatives are anti-Parkinson activity, antiarrhythmic and local anaesthetic effects, antimalarial activity, and central stimulation, but none of these properties has led to a therapeutic preparation. 

Pharmacological studies on aporphines have centred mainly around (—)-apomorphine (41) and its close relatives because this degradation product of morphine stimulates the dopaminergic system in rats and mice, and has anti-Parkinson activity. It also has a hypotensive effect and very recently has been shown... 

Memantine. 3,S-Dimethyltricyclo[3.3.I.I3 ]decan-1-amine 3,S-dimethyl-l-adamantanamine 1 -amino-3,5-dimethyladamantane DMAA D 145. C.jH N mol wt 179.31. C 80.38%, H 11.81%, N 7.81%. Deriv of adaman-tine, q.v.. with anti-parkinson activity. Prepn of the hydrochloride K. Gerzon et al. J. Med. Chem. 6, 760 (1963) of the free base and hydrochloride J. Mills, E. Krumkalns, UJS. pat. 3,391,142 (1968 to Lilly). GC and mass spec studies of memantine metabolites W. Wesemann et al, Arznei-mittel-Forsch. 27, 1471 (1977), Effects in parkinsonian patients P. -A. Fischer er at., Ibid, 1487. Series of articles on distribution, effects on neurobiological processes, clinical studies in control of micturition and limb muscle mobility ibid. 32, 1236-1276 (1982). Clinical studies as antispasmod-ic agent H. Rohde, Fortschr. Med. 100, 2023 (1982). Pharmacodynamics and pharmacokinetics W. Wesemann et al, Arzneimittel-Forsch. 33, 1122 (1983). 

N-unsubstituted sulphamates of the type 244 have been prepared by the reaction of the appropriate alcohol with sodium hydride in DMF with sulphamoyl chloride at 0-5 °C248. The compounds are reported to have anticonvulsant activity and are considered to be potential agents for the treatment of epilepsy. In addition, carbonic anhydrase activity was reported for the compounds and they are considered to be useful in the treatment of glaucoma. A series of 8a-substituted ergoline derivatives (245) were shown to have anti-Parkinson activity and inhibited prolactim secretion249. 

The modifier in these cases seems to generate enantioselective sites at the metal surface and helps the molecule to adsorb in a preferred fashion so that the formation of only one stereo- product is possible. There are several milestones that have contributed to this state-of-the-art technology. Discovery of Wilkinson s catalyst led to the feasibility of asymmetric hydrogen transfer with the aid of an optically active Wilkinson-type catalyst for L-DOPA (Monsanto s anti-Parkinson disease drug) synthesis (Eqn. (21)). 

A classical example is the development of soluble chiral catalysts for homogenous asymmetric hydrogenation. The story began with the discovery of Wilkinson s catalyst [4]. In 1968, Horner [5] and Knowles [6], independently, reported the feasibility of asymmetric hydrogenations in the presence of optically active Wilkinson-type catalyst. Although the optical yields were rather low, further studies in this direction were the basis of the success of Monsanto s asymmetric synthesis of the anti-Parkinson s drug L-DOPA. The key steps of the synthesis are outlined in Scheme 11.1. 

Toxicity is remarkably low for a compound of such activity. In mice, the LDso value is about three times that of chlorpromazine [166] while none of the effects of the latter drug on the myocardium, liver, skin or eye have appeared in the studies of oxypertine. It is, however, still too early to appraise its chronic toxicity in man. As indicated earlier, dangerous interactions are likely to follow concurrent use of a MAO inhibitor, though simultaneous use of anti-Parkinsonism drugs, for example, to control the relatively minor extra-pyramidal symptoms seems to present no unusual problems. Hypotension may occasionally occur with high doses. 

Tolcapone [TOLE ka pone] is a nitrocatechol derivative that represents a new class of anti-Parkinson s drugs. It selectively and reversibly inhibits both peripheral and central catechol-O-methyl-transferase (COMT) (Figure 8.11). Normally, the methylation of levo-dopa by COMT to 3-O-methyldopa is a minor pathway for levodopa metabolism. However, when peripheral dopamine decarboxylase activity is inhibited by carbidopa, a significant concentration of 3-O-methyldopa is formed that competes with levodopa for active transport into the CNS. Inhibition of COMT by tolcapone leads to decreased plasma concentrations of 3-O-methyldopa, increased central uptake of levodopa, and greater concentrations of brain dopamine. Tolcapone has been demonstrated to reduce the frequency of the on-off phenomenon. 

Amona muricata L. -graviola Tranquilizer No information Caboclos [59] Acetogenins [86,87] neurotoxic benzylisoquinoline derivatives [88] essential oil [89,90] alkaloids [91,92] flavonoids and terpenoids [93] striatal neurodegeneration [252] atypical parkinsonism [253] anti leishmanial activity [254] antidepressive activity [91]... 

More than 90% of biomolecules exhibit chirality. Many pharmaceutical products contain different chiral forms of drugs, some of which are harmful or ineffective. For example, one form of the drug naproxen has 28 times the anti-inflammatory activity of its enantiomer. In the synthetic form of dopamine used to treat Parkinson s disease one isomer acts on the nerve cells to control the patient s tremors whilst the other enantiomer is toxic. 

Dopamine Inhibitory, multiple subtypes (5+)—G-protein finked to c AMP activities T by CNS stimulants and anti-Parkinson drugs, 4- by antipsychotics. 

Many anti-psychotic drugs have what are called Parkinsonian or extra-pyramidal side effects. These are abnormalities of movement that resemble Parkinson s disease (see page 211) and are due to the blocking of dopamine D2 receptors in the basal nuclei. Anti-psychotics that also have anti-cholinergic activity (for example pericyazine) cause fewer Parkinsonian side effects. 

As mentioned, GABA is an important neural transmitter and deficiencies in GABA are associated with diseases that exhibit neuromuscular dysfunction such as epilepsy, Huntington s disease and Parkinson s disease. S-Aminopentanoic acid (S-aminovaleric acid, DAVA) is also a neurotransmitter and used for treatment of neuromuscular disease. In at least one study, 3-alkyl-4-aminobutanoic acid derivatives were shown to be in vitro activators of f glutamic acid decarboxylase and they showed anti-convulsant activity. ... 

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