Anti-Parkinson

TM 311 is in fact the anti-Parkinson s disease compound trihexylphenidyl and is made industrially by route c (Tedder, volume 5, p.418). 

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). 

Bradykinesia is slowness and poverty of movement. Anti-Parkinson Drugs... 

Dopaminergic System Anti-Parkinson Drugs a-Adrenergic System... 

Catechol-O-Methyltransferases Anti-Parkinson Dtugs Antipsychotic Dtugs... 

SUM MARY DRUG TABLE ANTI PARKINSON ISM DRUGS... 

Suggest a synthesis fpr the anti-Parkinson drug orphenadrine (23). 

More typical examples are the amino ethers (3) used as anti-histamine or anti-Parkinson drugs according to the substituents. These are obviously derived from the alcohols (4) which are made from an aryl Grignard reagent and a benzaldehyde. Either starting material may bear the substituent X the choice can be made according to availability and so that side reactions are avoided,... 

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. 

DKP drugs, which were developed as analgesics and anti-Parkinson s agents, have entered the clinical trial phase. ... 

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. 

Youdim, M.B.H. (2006) The path from anti Parkinson drug selegiline and rasagiline to multifunctional neuroprotective anti... 

For many of the drugs associated with hepatotoxicity, there are examples of structurally related drugs which are latent to bioactivation and toxicity because of the absence of the toxicophore or the existence of alternate metabolic pathways. For example, the hepatotoxicity associated with the use of the anti-Parkinson s agent tolcapone does not occur with the structurally related drug entacapone, despite administration at doses similar to tolcapone (200-1000 mg QD). This disparity may be explained in part by the observation that entacapone does not succumb to the bioactivation reactions of tolcapone in humans (Scheme 15.3) [35]. It is also noteworthy that tolcapone but not entacapone is a potent uncoupler of oxidative... 

Tricyclic antidepressants are notorious for their risk to be involved in drug-drug interactions. Additive anticholinergic effects can be expected in combination with antihistamines, antipsychotics and anticholinergic-type anti-Parkinson agents. Hepatic enzyme-inducing agents increase their hepatic metabolism while enzyme inhibitors may potentiate the effects of tricyclics. Concomitant use with monoamine oxidase inhibitors will produce hypertension, hyperpyrexia and convulsions. 

Medicinal chemistry has many examples of the development of successful therapeutics based on an exploration of endogenous compounds. The treatment of diabetes mellitus, for example, is based upon the administration of insulin, the hormone that is functionally deficient in this disease. The current treatment of Parkinson s disease is based upon the observation that the symptoms of Parkinson s disease arise from a deficiency of dopamine, an endogenous molecule within the human brain. Since dopamine cannot be given as a drug since it fails to cross the blood-brain barrier and enter the brain, its biosynthetic precursor, L-DOPA, has been successfully developed as an anti-Parkinson s drug. Analogously, the symptoms of Alzheimer s disease arise from a relative deficiency of acetylcholine within the brain. Current therapies for Alzheimer s-type dementia are based upon the administration of cholinesterase... 

N. P. Quinn (1984). Anti-Parkinson drugs today. Drugs 28 236-262. 

Levodopa degraded in gut prior to reaching sites of absorption. Agents that alter gastrointestinal motility may alter degree of intraluminal degradation. Anti-parkinsonism effect of levodopa susceptible to inhibition by other drugs. 

Wesemann, W., Sturm, G., Funfgeld, E. W. Distribution of metabolism of the potential anti-Parkinson drug memantine in the human, J. Neural Transm. 1980, 16, Suppl., 143-148. 

---