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Glycosyl derivatives of dopamine and L-dopa as anti-Parkinson prodrugs: synthesis, pharmacological activity and in vitro stability studies.
J Drug Target. 2003 Jan; 11(1):25-36.JD

Abstract

Novel glycosyl derivatives of dopamine and L-dopa (I-IV) are synthesized in order to overcome the problem of blood-brain barrier low permeability of dopamine and of low bioavailability of its precursor L-dopa. Esters synthesized link dopamine and L-dopa, by a succinyl linker, to C-3 position of glucose (I and II) and to C-6 of galactose (II and IV). The chemical and enzymatic stabilities of esters synthesized were evaluated in order to determine both their stability in aqueous medium and their feasibility in undergoing enzymatic cleavage by rat plasma to regenerate the original drug. Furthermore, we have shown the central effects of esters I-IV on classic dopaminergic models, such as morphine induced locomotion and reserpine-induced hypolocomotion. From the result obtained compounds I-IV appeared moderately stable in a pH 7.4 buffered solution and in rat plasma. Furthermore, pharmacological studies showed that both dopamine derivatives (I and II) were equiactive in reversing reserpine-induced hypolocomotion in rats, and both were more active than L-dopa or ester III and IV, while II and III were more potent in reducing morphine-induced locomotion than I and IV. The minimal vascular effects of these derivatives allow us to underline the possibility to use them in pathologies, such as Parkinson disease, characterised by an evident decreasing of dopamine concentration in the brain.

Authors+Show Affiliations

Department of Pharmaceutical Sciences, School of Pharmacy, University of Catania, Viale A.Doria no 6, 95125 Catania, Italy. boninaf@unict.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

12852438

Citation

Bonina, Francesco, et al. "Glycosyl Derivatives of Dopamine and L-dopa as anti-Parkinson Prodrugs: Synthesis, Pharmacological Activity and in Vitro Stability Studies." Journal of Drug Targeting, vol. 11, no. 1, 2003, pp. 25-36.
Bonina F, Puglia C, Rimoli MG, et al. Glycosyl derivatives of dopamine and L-dopa as anti-Parkinson prodrugs: synthesis, pharmacological activity and in vitro stability studies. J Drug Target. 2003;11(1):25-36.
Bonina, F., Puglia, C., Rimoli, M. G., Melisi, D., Boatto, G., Nieddu, M., Calignano, A., La Rana, G., & De Caprariis, P. (2003). Glycosyl derivatives of dopamine and L-dopa as anti-Parkinson prodrugs: synthesis, pharmacological activity and in vitro stability studies. Journal of Drug Targeting, 11(1), 25-36.
Bonina F, et al. Glycosyl Derivatives of Dopamine and L-dopa as anti-Parkinson Prodrugs: Synthesis, Pharmacological Activity and in Vitro Stability Studies. J Drug Target. 2003;11(1):25-36. PubMed PMID: 12852438.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glycosyl derivatives of dopamine and L-dopa as anti-Parkinson prodrugs: synthesis, pharmacological activity and in vitro stability studies. AU - Bonina,Francesco, AU - Puglia,Carmelo, AU - Rimoli,Maria Grazia, AU - Melisi,Daniela, AU - Boatto,Giampiero, AU - Nieddu,Maria, AU - Calignano,Antonio, AU - La Rana,Giovanna, AU - De Caprariis,Paolo, PY - 2003/7/11/pubmed PY - 2003/8/2/medline PY - 2003/7/11/entrez SP - 25 EP - 36 JF - Journal of drug targeting JO - J Drug Target VL - 11 IS - 1 N2 - Novel glycosyl derivatives of dopamine and L-dopa (I-IV) are synthesized in order to overcome the problem of blood-brain barrier low permeability of dopamine and of low bioavailability of its precursor L-dopa. Esters synthesized link dopamine and L-dopa, by a succinyl linker, to C-3 position of glucose (I and II) and to C-6 of galactose (II and IV). The chemical and enzymatic stabilities of esters synthesized were evaluated in order to determine both their stability in aqueous medium and their feasibility in undergoing enzymatic cleavage by rat plasma to regenerate the original drug. Furthermore, we have shown the central effects of esters I-IV on classic dopaminergic models, such as morphine induced locomotion and reserpine-induced hypolocomotion. From the result obtained compounds I-IV appeared moderately stable in a pH 7.4 buffered solution and in rat plasma. Furthermore, pharmacological studies showed that both dopamine derivatives (I and II) were equiactive in reversing reserpine-induced hypolocomotion in rats, and both were more active than L-dopa or ester III and IV, while II and III were more potent in reducing morphine-induced locomotion than I and IV. The minimal vascular effects of these derivatives allow us to underline the possibility to use them in pathologies, such as Parkinson disease, characterised by an evident decreasing of dopamine concentration in the brain. SN - 1061-186X UR - https://www.unboundmedicine.com/medline/citation/12852438/Glycosyl_derivatives_of_dopamine_and_L_dopa_as_anti_Parkinson_prodrugs:_synthesis_pharmacological_activity_and_in_vitro_stability_studies_ L2 - https://www.tandfonline.com/doi/full/10.1080/1061186031000086090 DB - PRIME DP - Unbound Medicine ER -