A New Type of Prodrug of Catecholamines:  An Opportunity To Improve the Treatment of Parkinson's Disease

Venhuis, BJ; Rodenhuis, N; Wikstrom, HV; Wustrow, David; Meltzer, Leonard T.; Wise, Lawrence D.; Johnson, SJ; Ta, Pugsley; Sundell, Staffan; Dijkstra, Durk

doi:10.1021/jm0209634

Cited by 5 publications

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“…With compound (S)-PD148903 (5.46), we encounter our first example of a redox-activated bioprecursor, in this case a biooxidative agent [75]. With compound (S)-PD148903 (5.46), we encounter our first example of a redox-activated bioprecursor, in this case a biooxidative agent [75].…”

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confidence: 99%

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

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Kraemer

2009

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The Part 5 of our biochemical introduction to drug metabolism presents the pharmacological and toxicological consequences of drug and xenobiotic metabolism. As we have already shown [1 -5] and discuss here with specific focus, the consequences of the biotransformation of foreign compounds explain to a large extent the immense significance this discipline has acquired. When it comes to drug metabolism, its consequences are of utmost relevance in fields such as drug discovery and development, clinical pharmacology and toxicology, and therapeutics. The same relevance is now recognized to xenobiotic metabolism in, e.g., agrochemistry and food chemistry, industrial hygiene, workplace safety, and environmental welfare.Presenting the pharmacological and toxicological consequences of drug and xenobiotic metabolism can be achieved by focusing on rules and general principles, with a high risk of remaining abstract and failing to impress readers. Or it can be done with examples only, with the consequence that readers will remember fragmental data which may not help them to generalize and reason by analogy. The didactic approach followed here is simply the middle course, whereby we start with principles and illustrate them with examples, while, at other occasions, discussing illustrative cases from which principles are then derived.

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Section: Fig 524mentioning

confidence: 99%

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

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Kraemer

2009

ChemInform

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“…It is thus very likely that an orally active DA D 1 /D 2 agonist, mimicking the pharmacological and clinical effects of apomorphine, would be a fierce competitor to L-DOPA for the treatment of Parkinson's disease. The novel enone prodrug S-PD148903 or one of its analogues could meet these criteria …”

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“…Synthesis. The two-step synthesis of PD148903, isolation and resolution, to give (−)-PD148903 and (+)-PD148903 are remarkably simple (Scheme ). ,, A Mannich type reaction generates an intermediate structure that, without purification, is reduced to racemic PD148903. The desired active enantiomer is crystallized from the reaction mixture using enantiomerically pure ditoluyltartaric acid.…”

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“…In vitro, the racemic prodrug (PD148903) has no binding affinity for the DA receptor family. However, biochemical and behavioral experiments in vivo proved that the prodrug is converted to a DA agonist. ,, We studied the pharmacological effects of the separated enantiomers by measuring their effects on the endogenous DA levels in the corpus striatum, the brain area of interest in Parkinson's disease, using microdialysis in freely moving rats. , Because microdialysis is a presynaptic model to investigate the pharmacological effect of a DA agonist, it is expressed as a decrease of the endogenous DA levels. For S-PD148903, a significant decrease of 50% and 70% of control values was observed after administration of 0.4 and 1.2 μmol kg -1 po, respectively (Figure ).…”

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“…The striatal presence of a catecholamine was observed only after administration of S-PD148903, indicating an enantioselective bioactivation of S-PD148903 or an enantioselective delivery of the catecholamine. Since we previously reported some close analogues of PD148903 that also induced dopaminergic behavior in vivo, bioactivation to a hydroxylated aminotetralin may be a general feature of this type of compounds . Since S-PD148903 is effective in a rat model of Parkinson's disease, S-PD148903 or one of its analogues could be of use in the treatment of Parkinson's disease.…”

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A New Type of Prodrug of Catecholamines: An Opportunity to Improve the Treatment of Parkinson's Disease

et al. 2002

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After decades of research around dopamine agonists, we have found a promising compound in S-PD148903 that represents a new type of prodrug, which in the rat is bioactivated to the catecholamine S-5,6-diOH-DPAT, known to display mixed dopamine D(1)/D(2) receptor agonist properties just like apomorphine. This prodrug has an enone structure which by an oxidative bioactivation mechanism is converted to the corresponding catechol and is delivered enantioselectively into the CNS. This novel concept has the potential to revolutionize the treatment of Parkinson's disease by competing with L-DOPA, the current treatment of choice.

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Orally Active Analogues of the Dopaminergic Prodrug 6-(N,N-Di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one: Synthesis and Pharmacological Activity

et al. 2003

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A series of analogues of 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one (6), an enone prodrug of the mixed DA D(1)/D(2) agonist 5,6-diOH-DPAT (2), was synthesized. The pharmacological profiles of these new enones and their in vivo pharmacological activities were investigated in the Ungerstedt rat rotation model for Parkinson's disease. At 0.1 mg kg(-1) po, the N-methyl-N-n-propyl (12) and the N-ethyl-N-propyl (13) analogues induced pronounced and long lasting pharmacological effects. The pharmacological profile of enone 12 was found to be similar to that of 6, while enone 13 was significantly more potent than 6 (p < 0.01). Analyses of rat brains after the administration of (-)-6 and 13 indicated the presence of hydroxylated metabolites of the parent enones. It is speculated that such metabolites are alpha'-hydroxylated enones that may constitute the first step in the formation of the corresponding catechols.

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A New Type of Prodrug of Catecholamines: An Opportunity To Improve the Treatment of Parkinson's Disease

Cited by 5 publications

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ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

A New Type of Prodrug of Catecholamines: An Opportunity to Improve the Treatment of Parkinson's Disease

Orally Active Analogues of the Dopaminergic Prodrug 6-(N,N-Di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one: Synthesis and Pharmacological Activity

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