Synthesis and Study of<scp>l</scp>-Dopa−Glutathione Codrugs as New Anti-Parkinson Agents with Free Radical Scavenging Properties

Pinnen, Francesco; Cacciatore, Ivana; Cornacchia, Catia; Sozio, Piera; Iannitelli, Antonio; Costa, Mara; Pecci, Laura; Nasuti, Cinzia; Cantalamessa, Franco; Stefano, Antonio Di

doi:10.1021/jm070037v

Cited by 61 publications

(40 citation statements)

References 43 publications

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“…The series of molecular combinations, in which LD is linked covalently via an amide bond with GSH (105-108), has been also evaluated as potential anti-Parkinson agents with antioxidant properties [79].…”

Section: Codrugs Of Ldmentioning

confidence: 99%

L-Dopa Prodrugs: An Overview of Trends for Improving Parkinsons Disease Treatment

Stefano

Sozio²,

Cerasa³

et al. 2011

CPD

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L-Dopa is the mainstay of Parkinson's disease therapy; this drug is usually administered orally, but it is extensively metabolized in the gastrointestinal tract, so that relatively little arrives in the bloodstream as intact L-Dopa. The peripheral conversion of L-Dopa by amino acid decarboxylase to dopamine is responsible for the typical gastrointestinal and cardiovascular side effects. To minimize the conversion to dopamine outside the central nervous system, L-Dopa is usually given in combination with peripheral inhibitors of amino acid decarboxylase. In spite of that, other central nervous side effects such as dyskinesia, on-off phenomenon and end-of-dose deterioration still remain. The main factors responsible for the poor bioavailability are the drug's physical-chemical properties: low water and lipid solubility, resulting in unfavorable partition, and the high susceptibility to chemical and enzymatic degradation. Starting from these considerations the prodrug approach has been applied to L-Dopa in order to overcome its metabolism problems and to improve its bioavailability. The goal of this paper is to provide the reader with a critical overview on L-Dopa prodrugs here classified according to the nature of the main chemical modification on L-Dopa backbone that led to the formation of the desired derivative.

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Section: Codrugs Of Ldmentioning

confidence: 99%

L-Dopa Prodrugs: An Overview of Trends for Improving Parkinsons Disease Treatment

Stefano

Sozio²,

Cerasa³

et al. 2011

CPD

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“…These principles of network-based, multitarget, and (by preference) early intervention apply to other complex CNS disorders such as fibromyalgia, 264 bipolar disorder, 265 Parkinson's disease, 266,267 and Alzheimer's dis-…”

Section: Comparison Of Multitarget Agents To Drug Associationsmentioning

confidence: 99%

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

Millan¹

2009

Neurotherapeutics

180

123

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Summary:The past decade of efforts to find improved treatment for major depression has been dominated by genomedriven programs of rational drug discovery directed toward highly selective ligands for nonmonoaminergic agents. Selective drugs may prove beneficial for specific symptoms, for certain patient subpopulations, or both. However, network analyses of the brain and its dysfunction suggest that agents with multiple and complementary modes of action are more likely to show broad-based efficacy against core and comorbid symptoms of depression. Strategies for improved multitarget exploitation of monoaminergic mechanisms include triple inhibitors of dopamine, serotonin (5-HT) and noradrenaline reuptake, and drugs interfering with feedback actions of monoamines at inhibitory 5-HT 1A , 5-HT 1B and possibly 5-HT 5A and 5-HT 7 receptors. Specific subsets of postsynaptic 5-HT receptors mediating antidepressant actions are under study (e.g., 5-HT 4 and 5-HT 6 ). Association of a clinically characterized antidepressant mechanism with a nonmonoaminergic component of activity is an attractive strategy. For example, agomelatine (a melatonin agonist/5-HT 2C antagonist) has clinically proven activity in major depression. Dual neurokinin 1 antagonists/5-HT reuptake inhibitors (SRIs) and melanocortin 4 antagonists/SRIs should display advantages over their selective counterparts, and histamine H 3 antagonists/SRIs, GABA B antagonists/SRIs, glutamatergic/SRIs, and cholinergic agents/SRIs may counter the compromised cognitive function of depression. Finally, drugs that suppress 5-HT reuptake and blunt hypothalamo-pituitary-adrenocorticotrophic axis overdrive, or that act at intracellular proteins such as GSK-3␤, may abrogate the negative effects of chronic stress on mood and neuronal integrity. This review discusses the discovery and development of dual-and tripleacting antidepressants, focusing on novel concepts and new drugs disclosed over the last 2 to 3 years.

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“…l-Dopa wurde über eine Amidbindung an GSH gebunden (Abbildung 5 H); die orale Verabreichung der Konjugate an Ratten führte zu einer nachhaltigen Freisetzung von l-Dopa und Dopamin im Gehirn, wodurch die Konzentration dieser beiden Verbindungen gegenüber der Verabreichung einer äquimolaren Dosis Dopamin erhçht wurde. [57] More et al [58] …”

Section: Chemisches Freisetzungssystem (Cds)unclassified

Schleuservermittelter Transport von Wirkstoffen ins Gehirn

2011

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Während des letzten Jahrzehnts wurden im Bereich der Wirkstofffreisetzung wesentliche Fortschritte erzielt. Die Behandlung von Gehirnerkrankungen bleibt aber wegen der Blut‐Hirn‐Schranke (BHS; blood–brain barrier) noch immer eine große Herausforderung. Diese Struktur schränkt den Zugang von Wirkstoffen zu ihrem Wirkort im Zentralnervensystem stark ein. Es wurden verschiedene Strategien vorgeschlagen, um den Transport von Wirkstoffen über die BHS zu verstärken. In diesem Aufsatz konzentrieren wir uns auf einen vektorvermittelten Ansatz, bei dem der Wirkstoff an ein Schleusermolekül gekuppelt wird, das die Fähigkeit hat, die BHS zu überqueren und die Substanz ins Gehirn abzugeben.

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Synthesis and Study ofl-Dopa−Glutathione Codrugs as New Anti-Parkinson Agents with Free Radical Scavenging Properties

Cited by 61 publications

References 43 publications

L-Dopa Prodrugs: An Overview of Trends for Improving Parkinsons Disease Treatment

L-Dopa Prodrugs: An Overview of Trends for Improving Parkinsons Disease Treatment

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

Schleuservermittelter Transport von Wirkstoffen ins Gehirn

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