Dopamine prodrug

Dopamine, a vasodilator, has been widely used for treatment of acute circulatory failure. However, since dopamine is rapidly metabolized when administered orally, its use has been limited to intravenous infusion. Murata et al., studied the bioavailability and the pharmacokinetics of orally administered dopamine (DA). The oral administration of DA to dogs resulted in an absolute bioavailability of approximately 3%. To minimize the extensive first-pass metabolism of DA, a dopamine prodrug, V-(/V-acetyl-l-mcLhionyl)-o,o-bis(cLhoxycarbonyl)dopamine (TA-870), was synthesized [28] (Fig. 6). Since DA is a substrate for both mono-... 

K Murata, N Kazuo, K Kohano, MJ Sanejirna. Bioavailability and pharmacokinetics of an oral dopamine prodrug in dogs. J Pharm Sci 78(10) 812-814,... 

I Yamaguchi, S Nishiyama, S Akimato, A Yoshiaki, M Yoshikawa, H Nakajima. A novel orally active dopamine prodrug TA-870. I. Renal and cardiovascular ef-... 

H. Sanada, L. D. Asico, S. Shigetomi, K. Tanaka, S. Niimura, H. Watanabe, D. S. Goldstein, R. A. Felder, The Effect of Docarpamine, a Dopamine Prodrug, on Blood Pressure and Catecholamine Levels in Spontaneously Hypertensive Rats , Clin. Exp. Hyper-tens. 2000, 22, 419 - 429. 

Mechanism of Action A dopamine prodrug that is converted to dopamine in basal ganglia. Increases dopamine concentrations in the brain, inhibiting hyperactive cholinergic activity. Therapeutic Effect Decreases signs and symptoms of Parkinson s disease. 

A device for retention of a dopamine prodrug into the central nervous system has been designed by the synthesis on N-methyl-dihydronicotinoyl amides of dopamine 3,4-0-diesters, such as 23, which are converted into a quaternary pyridinium derivative by oxidation, and thereby retained inside the blood-brain barrier [19]. Only modest dopamine-like activity was observed, and this may due to a slow rate of enzymatic hydrolysis of the amide bond joining the dopamine and the pyridinium moieties. 

Docarpamine was also shown to be an orally effective peripheral dopamine prodrug, at doses higher than ibopamine [13, 23], and it is used in Japan for weaning patients from i.v. dopamine infusion in severe heart failure. 

The dopamine prodrug levodopa remains the treatment option for PD, however, long-term levodopa therapy leads to dyskinesia. Alternatives for early PD therapy include monoamine oxidase B inhibitors, dopamine agonists, catechol-O-methyltransferase (COMT) inhibitors, and amantadine (Hauser and Zesiewicz,... 

Drugs used in parkinsonism Dopamine prodrug Levodopa ... 

An interesting example of the above difference is l-DOPA 4, which is used in the treatment of Parkinson s disease. The active drug is the achiral compound dopamine formed from 4 via in vivo decarboxylation. As dopamine cannot cross the blood-brain barrier to reach the required site of action, the prodrug 4 is administered. Enzyme-catalyzed in vivo decarboxylation releases the drug in its active form (dopamine). The enzyme l-DOPA decarboxylase, however, discriminates the stereoisomers of DOPA specifically and only decarboxylates the L-enantiomer of 4. It is therefore essential to administer DOPA in its pure L-form. Otherwise, the accumulation of d-DOPA, which cannot be metabolized by enzymes in the human body, may be dangerous. Currently l-DOPA is prepared on an industrial scale via asymmetric catalytic hydrogenation. 

The second illustration of the interest of /V-monosubsti luted carbamates is in prodrugs of (-)-3-(3-hydroxyphenyl)-N-propylpiperidine, also known as (-)-3-PPP [163], This presynaptic dopamine autoreceptor agonist readily crosses the blood-brain barrier but is orally poorly bioavailable. The bioavailability of the drug was not improved in the majority of a large and structurally very diverse series of prodrugs. However, a few /V-(subsli luted phe-nyl)carbamates stood out as remarkable exceptions. While the AT-phenylcar-bamate and AT-(4-chlorophenyl)carbamates were poorly bioavailable, the iV-(4-isopropylphenyl)carbamate (8.129), AT-(4-ethoxyphenyl)carbamate, and iV-(3,4-dimethoxyphenyl)carbamate each exhibited good bioavailability. Pro-... 

D. R. Cooper, C. Marrel, H. van de Waterbeemd, B. Testa, P. Jenner, C. D. Marsden, l-Dopa Esters as Potential Prodrugs Behavioural Activity in Experimental Models of Parkinson s Disease , J. Pharm. Pharmacol. 1987, 39, 627 - 635 D. R. Cooper, C. Marrel, H. van de Waterbeemd, B. Testa, P. Jenner, C. D. Marsden, L-Dopa Esters as Potential Prodrugs Effect on Brain Concentration of Dopamine Metabolites in Reserpi-nized Mice , J. Pharm. Pharmacol. 1987, 39, 809-818. 

I. den Daas, P. de Boer, P. G. Tepper, H. Rollema, A. S. Horn, Orally Active Carbamate Prodrugs of the Selective Dopamine Agonist N-0437 In-vivo Activities in the 6-OHDA Turning Model and in-vitro Activities , J. Pharm. Pharmacol. 1991, 43, 11 - 16. 

S. O. Thorberg, S. Berg, J. Lundstrom, B. Pettersson, A. Wijkstrom, D. Sanchez, P. Lind-berg, J. L. G. Nilsson, Carbamate Ester Derivatives as Potential Prodrugs of the Pre-synaptic Dopamine Autoreceptor Agonist (-)-3-(3-Hydroxyphenyl)-A-propylpiperidine J. Med. Chem. 1987, 30, 2008-2012. 

Since Parkinson s disease arises from a deficiency of DA in the brain, the logical treatment is to replace the DA. Unfortunately, dopamine replacement therapy cannot be done with DA because it does not cross the blood-brain barrier. However, high doses (3-8 g/day, orally) of L(-)-DOPA (levodopa), a prodrug of DA, have a remarkable effect on the akinesia and rigidity. The side effects of such enormous doses are numerous and unpleasant, consisting initially of nausea and vomiting and later of uncontrolled movements (limb dyskinesias). The simultaneous administration of carbidopa (4.75) or benserazide (4.76)—peripheral DOPA decarboxylase inhibitors—allows the administration of smaller doses, and also prevents the metabolic formation of peripheral DA, which can act as an emetic at the vomiting center in the brainstem where the blood-brain barrier is not very effective and can be penetrated by peripheral DA. 

Design a prodrug that could be used to transport the diethanoate ester of dopamine (A) across the blood-brain barrier. Show by means of notes and equations how this prodrug would function. 

More recently, we initiated a series of experiments to test the activity of new derivatives of apomorphine, some of which had been classified as dopamine agonists or antagonists (40-45). Pretreatment of rats with 50 or 100 ug/100 g body weight of (-)N-n-propylnorapomorphine (NPA) or the prodrug (-)... 

Also, positive outcome was achieved after i.p. administration of the liposomal formulation of an L-dopa prodrug derivative to rats [218], It was shown that the level of dopamine in rat striatum was 2.5-fold higher to what was obtained after i.p. administration of L-dopa or the free prodrug itself. 

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