Novel L-Dopa and dopamine prodrugs containing a 2-phenyl-imidazopyridine moiety.
OBJECTIVE
The aim of this study was to gain insight into the feasibility of enhancing the delivery of L-Dopa and dopamine to the brain by linking these neurotransmitters and L-Dopa ethyl ester to 2-phenyl-3-carboxymethyl-imidazopyridine compounds giving rise to the so-called Dopimid compounds.


METHODS
A number of Dopimid compounds were synthesized and both stability and binding studies to dopaminergic and benzodiazepine receptors were performed. To evaluate whether Dopimid compounds are P-gp substrates, [(3)H]ritonavir uptake experiments and bi-directional transport studies on confluent MDCKII-MDR1 monolayers were carried out. The brain penetration properties of Dopimid compounds were estimated by the Clark's computational model and evaluated by investigation of their transport across BBMECs monolayers. The dopamine levels following the intraperitoneal administration of the selected Dopimid compounds were measured in vivo by using brain microdialysis in rat.


RESULTS
Tested compounds were adequately stable in solution buffered at pH 7.4 but undergo faster cleavage in dilute rat serum at 37 degrees C. Receptor binding studies showed that Dopimid compounds are essentially devoid of affinity for dopaminergic and benzodiazepine receptors. [(3)H]ritonavir uptake experiments indicated that selected Dopimid compounds, like L-Dopa and dopamine hydrochloride, are not substrates of P-gp and it was also confirmed by bi-directional transport experiments across MDCKII-MDR1 monolayers. By Clark's model a significant brain penetration was deduced for L-Dopa ethyl ester and dopamine derivatives. Transport studies involving BBMECs monolayers indicated that some of these compounds should be able to cross the BBB. Interestingly, the rank order of apparent permeability (P (app)) values observed in these assays parallels that calculated by the computational approach. Brain microdialysis experiments in rat showed that intraperitoneal acute administration of some Dopimid compounds induced a dose-dependent increase in cortical dopamine output.


CONCLUSIONS
Based on these results, it may be concluded that some Dopimid compounds can be proposed as novel L-Dopa and dopamine prodrugs.
Denora
Nunzio
N
Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Via Orabona 4, 70125, Bari, Italy.
Laquintana
Valentino
V
Lopedota
Angela
A
Serra
Mariangela
M
Dazzi
Laura
L
Biggio
Giovanni
G
Pal
Dhananjay
D
Mitra
Ashim K
AK
Latrofa
Andrea
A
Trapani
Giuseppe
G
Liso
Gaetano
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000166:cytology / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D002199:Capillary Permeability; D002417:Cattle; D002460:Cell Line; D003198:Computer Simulation; D004285:Dogs; D004298:Dopamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D042783:Endothelial Cells / Q000378:metabolism; D005240:Feasibility Studies; D007093:Imidazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D007274:Injections, Intraperitoneal; D007980:Levodopa / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D017551:Microdialysis; D008954:Models, Biological; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D019438:Ritonavir / Q000378:metabolism; D013997:Time Factors; D014316:Tritium
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000978:Antiparkinson Agents; D007093:Imidazoles; D011355:Prodrugs; D011725:Pyridines; D011954:Receptors, Dopamine; D011963:Receptors, GABA-A; D014316:Tritium; D007980:Levodopa; D019438:Ritonavir; D004298:Dopamine