Design, synthesis, and preliminary pharmacological evaluation of new imidazolinones as L-DOPA prodrugs. 2010

Gianfabio Giorgioni, and Francesco Claudi, and Sabrina Ruggieri, and Massimo Ricciutelli, and Giovanni F Palmieri, and Antonio Di Stefano, and Piera Sozio, and Laura S Cerasa, and Annalisa Chiavaroli, and Claudio Ferrante, and Giustino Orlando, and Richard A Glennon
Dipartimento di Scienze Chimiche, Università di Camerino, via Sant'Agostino 1, 62032 Camerino, Italy. gianfabio.giorgioni@unicam.it

L-DOPA, the immediate biological precursor of dopamine, is still considered the drug of choice in the treatment of Parkinson's disease. However, therapy with L-DOPA is associated with a number of acute problems. With the aim to increase the bioavailability after oral administration, we designed a multi-protected L-DOPA prodrugs able to release the drug by both spontaneous chemical or enzyme catalyzed hydrolysis. The new compounds have been synthesized and preliminarily evaluated for their water solubility, log P, chemical stability, and enzymatic stability. The results indicate that the incorporation of the amino acidic moiety of L-DOPA into an imidazoline-4-one ring provides prodrugs sufficiently stable to potentially cross unchanged the acidic environment of the stomach, and to be absorbed from the intestine. They also might be able to release L-DOPA in human plasma after enzymatic hydrolysis. The ability of prodrugs 6a-b to increase basal levels of striatal DA, and influence brain neurochemistry associated with dopaminergic activity following oral administration, as well as the radical-scavenging activity against DPPH for compounds 6a-b and 15a are also reported.

UI MeSH Term Description Entries
D007093 Imidazoles Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).
D007700 Kinetics The rate dynamics in chemical or physical systems.
D007980 Levodopa The naturally occurring form of DIHYDROXYPHENYLALANINE and the immediate precursor of DOPAMINE. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to DOPAMINE. It is used for the treatment of PARKINSONIAN DISORDERS and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. L-Dopa,3-Hydroxy-L-tyrosine,Dopaflex,Dopar,L-3,4-Dihydroxyphenylalanine,Larodopa,Levopa,3 Hydroxy L tyrosine,L 3,4 Dihydroxyphenylalanine,L Dopa
D010300 Parkinson Disease A progressive, degenerative neurologic disease characterized by a TREMOR that is maximal at rest, retropulsion (i.e. a tendency to fall backwards), rigidity, stooped posture, slowness of voluntary movements, and a masklike facial expression. Pathologic features include loss of melanin containing neurons in the substantia nigra and other pigmented nuclei of the brainstem. LEWY BODIES are present in the substantia nigra and locus coeruleus but may also be found in a related condition (LEWY BODY DISEASE, DIFFUSE) characterized by dementia in combination with varying degrees of parkinsonism. (Adams et al., Principles of Neurology, 6th ed, p1059, pp1067-75) Idiopathic Parkinson Disease,Lewy Body Parkinson Disease,Paralysis Agitans,Primary Parkinsonism,Idiopathic Parkinson's Disease,Lewy Body Parkinson's Disease,Parkinson Disease, Idiopathic,Parkinson's Disease,Parkinson's Disease, Idiopathic,Parkinson's Disease, Lewy Body,Parkinsonism, Primary
D011355 Prodrugs A compound that, on administration, must undergo chemical conversion by metabolic processes before becoming the pharmacologically active drug for which it is a prodrug. Drug Precursor,Drug Precursors,Pro-Drug,Prodrug,Pro-Drugs,Precursor, Drug,Precursors, Drug,Pro Drug,Pro Drugs
D004298 Dopamine One of the catecholamine NEUROTRANSMITTERS in the brain. It is derived from TYROSINE and is the precursor to NOREPINEPHRINE and EPINEPHRINE. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of receptors (RECEPTORS, DOPAMINE) mediate its action. Hydroxytyramine,3,4-Dihydroxyphenethylamine,4-(2-Aminoethyl)-1,2-benzenediol,Dopamine Hydrochloride,Intropin,3,4 Dihydroxyphenethylamine,Hydrochloride, Dopamine
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006868 Hydrolysis The process of cleaving a chemical compound by the addition of a molecule of water.
D000284 Administration, Oral The giving of drugs, chemicals, or other substances by mouth. Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

Related Publications

Gianfabio Giorgioni, and Francesco Claudi, and Sabrina Ruggieri, and Massimo Ricciutelli, and Giovanni F Palmieri, and Antonio Di Stefano, and Piera Sozio, and Laura S Cerasa, and Annalisa Chiavaroli, and Claudio Ferrante, and Giustino Orlando, and Richard A Glennon
September 2010, European journal of medicinal chemistry,
Gianfabio Giorgioni, and Francesco Claudi, and Sabrina Ruggieri, and Massimo Ricciutelli, and Giovanni F Palmieri, and Antonio Di Stefano, and Piera Sozio, and Laura S Cerasa, and Annalisa Chiavaroli, and Claudio Ferrante, and Giustino Orlando, and Richard A Glennon
October 2007, Journal of medicinal chemistry,
Gianfabio Giorgioni, and Francesco Claudi, and Sabrina Ruggieri, and Massimo Ricciutelli, and Giovanni F Palmieri, and Antonio Di Stefano, and Piera Sozio, and Laura S Cerasa, and Annalisa Chiavaroli, and Claudio Ferrante, and Giustino Orlando, and Richard A Glennon
November 2006, Journal of medicinal chemistry,
Gianfabio Giorgioni, and Francesco Claudi, and Sabrina Ruggieri, and Massimo Ricciutelli, and Giovanni F Palmieri, and Antonio Di Stefano, and Piera Sozio, and Laura S Cerasa, and Annalisa Chiavaroli, and Claudio Ferrante, and Giustino Orlando, and Richard A Glennon
February 2008, Bioorganic & medicinal chemistry,
Gianfabio Giorgioni, and Francesco Claudi, and Sabrina Ruggieri, and Massimo Ricciutelli, and Giovanni F Palmieri, and Antonio Di Stefano, and Piera Sozio, and Laura S Cerasa, and Annalisa Chiavaroli, and Claudio Ferrante, and Giustino Orlando, and Richard A Glennon
January 2003, Journal of drug targeting,
Gianfabio Giorgioni, and Francesco Claudi, and Sabrina Ruggieri, and Massimo Ricciutelli, and Giovanni F Palmieri, and Antonio Di Stefano, and Piera Sozio, and Laura S Cerasa, and Annalisa Chiavaroli, and Claudio Ferrante, and Giustino Orlando, and Richard A Glennon
October 2013, Bioorganic & medicinal chemistry letters,
Gianfabio Giorgioni, and Francesco Claudi, and Sabrina Ruggieri, and Massimo Ricciutelli, and Giovanni F Palmieri, and Antonio Di Stefano, and Piera Sozio, and Laura S Cerasa, and Annalisa Chiavaroli, and Claudio Ferrante, and Giustino Orlando, and Richard A Glennon
December 2008, Bioorganic & medicinal chemistry,
Gianfabio Giorgioni, and Francesco Claudi, and Sabrina Ruggieri, and Massimo Ricciutelli, and Giovanni F Palmieri, and Antonio Di Stefano, and Piera Sozio, and Laura S Cerasa, and Annalisa Chiavaroli, and Claudio Ferrante, and Giustino Orlando, and Richard A Glennon
September 2019, Bioorganic & medicinal chemistry letters,
Gianfabio Giorgioni, and Francesco Claudi, and Sabrina Ruggieri, and Massimo Ricciutelli, and Giovanni F Palmieri, and Antonio Di Stefano, and Piera Sozio, and Laura S Cerasa, and Annalisa Chiavaroli, and Claudio Ferrante, and Giustino Orlando, and Richard A Glennon
December 2010, Journal of enzyme inhibition and medicinal chemistry,
Gianfabio Giorgioni, and Francesco Claudi, and Sabrina Ruggieri, and Massimo Ricciutelli, and Giovanni F Palmieri, and Antonio Di Stefano, and Piera Sozio, and Laura S Cerasa, and Annalisa Chiavaroli, and Claudio Ferrante, and Giustino Orlando, and Richard A Glennon
December 2023, Journal of medicinal chemistry,
Copied contents to your clipboard!