Glycosyl Derivatives of Dopamine and l -dopa as Anti-Parkinson Prodrugs: Synthesis, Pharmacological Activity and In Vitro Stability Studies

Bonina, Francesco; Puglia, Carmelo; Rimoli, Maria Grazia; Melisi, Daniela; Boatto, Gianpiero; Nieddu, Maria; Calignano, Antonio; Rana, Giovanna La; Caprariis, P. De

doi:10.1080/10611860305553

Cited by 35 publications

(46 citation statements)

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“…3 One strategy to improve poor drug uptake in the brain is to administer compounds as prodrugs that can be shuttled by transporters specifically expressed at the BBB. 4 Using this approach, researchers have succeeded in designing drug-carrier conjugates that can specifically interact with glucose transporters (GluT1), 5 amino acid transporters (LAT1), 6 and choline transporters, 7 thereby targeting the drugs to the brain. For cationic drugs, however, the transporters that may move them across BBB remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Brain Targeting by Dexibuprofen Prodrugs Modified with Ethanolamine-Related Structures

Zhou

Jiang

et al. 2015

J Cereb Blood Flow Metab

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The first molecular insights into how prodrugs modified with ethanolamine-related structures target the brain were generated using an in vitro BBB model and in situ perfusion technique. Prodrugs were delivered safely and efficiently to the brain through tight interaction with the anionic membrane of brain capillary endothelial cells, observed as a shift in zeta potential, followed by uptake into the cells. Prodrugs III and IV carrying primary and secondary amine modifications appeared to enter the brain via energyindependent passive diffusion. In contrast, besides the passive diffusion, prodrugs I and II carrying tertiary amine modifications also appeared to enter via an active process that was energy and pH dependent but was independent of sodium or membrane potential. This active process involved, at least in part, the pyrilamine-sensitive H + /OC antiporter, for which the N,N-diethyl-based compound II showed a much lower affinity than the N,N-dimethyl-based compound I, likely due to steric hindrance. These new insights into brain-targeting mechanisms may help guide efforts to design new prodrugs.

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Section: Introductionmentioning

confidence: 99%

Mechanism of Brain Targeting by Dexibuprofen Prodrugs Modified with Ethanolamine-Related Structures

Zhou

Jiang

et al. 2015

J Cereb Blood Flow Metab

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“…Similarly, the LD esters with C-3 position of glucose and C-6 position of galactose were synthesized (80 and 81 respectively) [50]. The obtained results indicate that compounds 80 and 81 appeared stable in buffered solution (pH 7.4) and in rat plasma.…”

Section: Glycosyl Prodrugs Of Ldmentioning

confidence: 92%

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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“…Furthermore, another shortcoming of dopamine is that although it cannot cross the BBB because of its polarity, it is nonetheless very active peripherally, thus causing a broad number of adverse cardiovascular effects. On the contrary, GALDA can reliably ward off peripheral side effects thanks to its stable plasma concentration determined by a gradual release of low amounts of dopamine directly in the CNS [12]. A recent study has demonstrated that galactosylation of N -nitro-L-arginine (NA), a non-selective nitric oxide synthase (NOS) inhibitor, generates the prodrug NAGAL Fig. (2).…”

Section: Brainmentioning

confidence: 98%

“…In particular, the hydroxyl group at the carbon 6'-position of the sugar is the most potential functional group to which the drug molecule attaches in order to maintain the affinity for the GLUT-1 transporter [8]. For instance, drugs as 7-chlorokynurenic acid [9], nipecotic acid [10] and dopamine [11][12] that have been conjugated with D-galactose have revealed enhanced activities in the CNS. Dopamine (DA) covalently linked to D-galactose (GALDA) by a succinic spacer Fig.…”

Section: Brainmentioning

confidence: 99%

“…Dopamine (DA) covalently linked to D-galactose (GALDA) by a succinic spacer Fig. (1), has proven to be a stable derivative as it displays significantly better effects on standard DA models, such as morphine-induced locomotion and reserpine-induced hypolocomotion, than the corresponding glycosyl derivative [12]. Indeed, unlike the latter derivative, D-galactose has a great affinity towards GLUT-1 and GLUT-3, the former located in the BBB and the latter in neurons [3].…”

Section: Brainmentioning

confidence: 99%

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D-Galactose as a Vector for Prodrug Design

Melisi¹,

Curcio²,

Luongo³

et al. 2011

CTMC

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D-galactose is a simple and natural compound that has mainly been exploited in prodrug strategies. Galactosyl prodrugs can be considered a good approach to reach different goals in clinical drug application, especially when traditional drugs are likely to fail therapeutically owing to reasons such as the lack of site specificity, toxicity, and chemical instability. Indeed, of paramount importance is their ability to increase the selectivity of the parent compound, a phenomenon that helps to reduce the incidence of adverse effects, while preserving intact the pharmacodynamic features of the parent drug. Study results have varied according to the type of linkage between the drug and the hydroxyl group exploited. By working with these parameters, researchers have been able not only to generate selective pharmacological targeting of brain, liver, and cancerous cells, but also to improve cellular permeability as well as the pharmacokinetic profile of parent drugs. This review describes the broad spectrum of possibilities for exploiting D-galactose as a vector for prodrug design and the synthetic strategies that allow its realization.

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Glycosyl Derivatives of Dopamine and l -dopa as Anti-Parkinson Prodrugs: Synthesis, Pharmacological Activity and In Vitro Stability Studies

Cited by 35 publications

References 0 publications

Mechanism of Brain Targeting by Dexibuprofen Prodrugs Modified with Ethanolamine-Related Structures

Mechanism of Brain Targeting by Dexibuprofen Prodrugs Modified with Ethanolamine-Related Structures

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

D-Galactose as a Vector for Prodrug Design

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