Design, synthesis, and preliminary pharmacological evaluation of new imidazolinones as L-DOPA prodrugs.
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.
Giorgioni
Gianfabio
G
Dipartimento di Scienze Chimiche, Università di Camerino, via Sant'Agostino 1, 62032 Camerino, Italy. gianfabio.giorgioni@unicam.it
Claudi
Francesco
F
Ruggieri
Sabrina
S
Ricciutelli
Massimo
M
Palmieri
Giovanni F
GF
Di Stefano
Antonio
A
Sozio
Piera
P
Cerasa
Laura S
LS
Chiavaroli
Annalisa
A
Ferrante
Claudio
C
Orlando
Giustino
G
Glennon
Richard A
RA
D000284:Administration, Oral; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D015195:Drug Design; D016166:Free Radical Scavengers / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D006868:Hydrolysis; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D007700:Kinetics; D007980:Levodopa / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats
D016166:Free Radical Scavengers; D007093:Imidazoles; D018696:Neuroprotective Agents; D011355:Prodrugs; D007980:Levodopa; D004298:Dopamine