Design, Synthesis and Brain Uptake of LAT1-Targeted Amino Acid Prodrugs of Dopamine

Peura, Lauri; Malmioja, Kalle; Huttunen, Kristiina M.; Leppänen, Jukka; Hämäläinen, Miia; Forsberg, Markus; Gynther, Mikko; Rautio, Jarkko; Laine, Krista

doi:10.1007/s11095-012-0966-3

Cited by 109 publications

(84 citation statements)

References 41 publications

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“…DA have recently been conjugated with different aminoacid derivatives, used as prodrug molecular carriers to target the brain by using their ability to interact with the large aminoacid transporter I (LAT I) [17]. DA combined with phenylalanine derivative presented the highest affinity for LAT I receptor and the best brain uptake after intravenous administration.…”

Section: Dss For Dopamine Deliverymentioning

confidence: 99%

Drug development in Parkinson's disease: From emerging molecules to innovative drug delivery systems

2013

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Current treatments for Parkinson's disease (PD) are aimed at addressing motor symptoms but there is no therapy focused on modifying the course of the disease.Successful treatment strategies have been so far limited and brain drug delivery remains a major challenge that restricts its treatment. This review provides an overview of the most promising emerging agents in the field of PD drug discovery, discussing improvements that have been made in brain drug delivery for PD. It will be shown that new approaches able to extend the length of the treatment, to release the drug in a continuous manner or to cross the blood brain barrier and target a specific region are still needed.Overall, the results reviewed here show that there is an urgent need to develop both symptomatic and disease-modifying treatments, giving priority to neuroprotective treatments. Promising perspectives are being provided in this field by rasagiline and by neurotrophic factors like glial cell line-derived neurotrophic factor. The identification of disease-relevant genes has also encouraged the search for disease-modifying therapies that function by identifying molecularly-targeted drugs. The advent of new molecular and cellular targets like α-synuclein, leucine-rich repeat serine/threonine protein kinase 2 or parkin, among others, will require innovative delivery therapies. In this regard, drug delivery systems (DDS) have shown great potential for improving the efficacy of conventional and new PD therapy and reducing its side effects. The new DDS discussed here, which include microparticles, nanoparticles and hydrogels among others, will probably open up possibilities that extend beyond symptomatic relief. However, further work needs to be done before DDS become a therapeutic option for PD patients.

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Section: Dss For Dopamine Deliverymentioning

confidence: 99%

Drug development in Parkinson's disease: From emerging molecules to innovative drug delivery systems

2013

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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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“…The LAT1 is primarily associated with transport of large amino acids such as tyrosine, thyroid hormones, especially triiodothyronine across the biological membranes in different tissues (44). In the last few decades, LAT1 has emerged as prime targets to deliver several drugs acting on central nervous system such as antiparkinson (L-Dopa), anticonvulsant, e.g., gabapentin and antidepressant (45). The LAT-1, an ideal target for drug delivery of wide variety drugs with slight structural modifications so that they become LAT-1 substrates have enhanced BBB penetration (Fig.…”

Section: Figmentioning

confidence: 99%

Targeting Therapeutics Across the Blood Brain Barrier (BBB), Prerequisite Towards Thrombolytic Therapy for Cerebrovascular Disorders—an Overview and Advancements

Pulicherla

Verma²

2015

AAPS PharmSciTech

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Cerebral tissues possess highly selective and dynamic protection known as blood brain barrier (BBB) that regulates brain homeostasis and provides protection against invading pathogens and various chemicals including drug molecules. Such natural protection strictly monitors entry of drug molecules often required for the management of several diseases and disorders including cerebral vascular and neurological disorders. However, in recent times, the ischemic cerebrovascular disease and clinical manifestation of acute arterial thrombosis are the most common causes of mortality and morbidity worldwide. The management of cerebral Ischemia requires immediate infusion of external thrombolytic into systemic circulation and must cross the blood brain barrier. The major challenge with available thrombolytic is their poor affinity towards the blood brain barrier and cerebral tissue subsequently. In the clinical practice, a high dose of thrombolytic often prescribed to deliver drugs across the blood brain barrier which results in drug dependent toxicity leading to damage of neuronal tissues. In recent times, more emphasis was given to utilize blood brain barrier transport mechanism to deliver drugs in neuronal tissue. The blood brain barrier expresses a series of receptor on membrane became an ideal target for selective drug delivery. In this review, the author has given more emphasis molecular biology of receptor on blood brain barrier and their potential as a carrier for drug molecules to cerebral tissues. Further, the use of nanoscale design and real-time monitoring for developed therapeutic to encounter drug dependent toxicity has been reviewed in this study.

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Design, Synthesis and Brain Uptake of LAT1-Targeted Amino Acid Prodrugs of Dopamine

Abstract: These results indicate that attachment of phenylalanine to a cationic drug via an amide bond from the meta-position of its aromatic ring could be highly applicable in prodrug design for LAT1-mediated CNS-delivery of not only anionic but also cationic polar drugs.

Cited by 109 publications

References 41 publications

Drug development in Parkinson's disease: From emerging molecules to innovative drug delivery systems

Drug development in Parkinson's disease: From emerging molecules to innovative drug delivery systems

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

Targeting Therapeutics Across the Blood Brain Barrier (BBB), Prerequisite Towards Thrombolytic Therapy for Cerebrovascular Disorders—an Overview and Advancements

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