title: Novel codrugs with GABAergic activity for dopamine delivery in the brain.
abstract: This study investigates the use of codrugs of the GABAergic agent 2-phenyl-imidazo[1,2-a]pyridinacetamide and dopamine (DA) or ethyl ester L-Dopa (LD) as a strategy to deliver DA and simultaneously activate GABA-receptors in the brain. For this purpose, both DA and LD ethyl ester were linked by carbamate bond to imidazo[1,2-a]pyridine acetamide moieties to yield two DA- and two LD-imidazopyridine derivatives. These compounds were evaluated in vitro to assess their stability, binding affinities and cell membrane transport, and in vivo to assess their bio-availability via microdialysis studies. The two DA derivatives were adequately stable in buffered solution, but underwent cleavage in diluted human serum. By contrast, the LD derivatives were unstable in buffered solution. Receptor binding studies showed that the DA-imidazopyridine carbamates had binding affinity for benzodiazepine receptors in the nanomolar range. Brain microdialysis experiments indicated that intraperitoneal administration of the DA derivatives sustained DA levels in rat striatum over a 4-h period. These results suggest that DA-imidazopyridine carbamates are new DA codrugs with potential application for DA replacement therapy.
authors.affiliation: Department of Pharmacy, University of Bari, Bari 70125, Italy.
authors.forename: Nunzio
authors.initials: N
authors.lastname: Denora
authors.forename: Tommaso
authors.initials: T
authors.lastname: Cassano
authors.forename: Valentino
authors.initials: V
authors.lastname: Laquintana
authors.forename: Antonio
authors.initials: A
authors.lastname: Lopalco
authors.forename: Adriana
authors.initials: A
authors.lastname: Trapani
authors.forename: Concetta Stefania
authors.initials: CS
authors.lastname: Cimmino
authors.forename: Leonardo
authors.initials: L
authors.lastname: Laconca
authors.forename: Andrea
authors.initials: A
authors.lastname: Giuffrida
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Trapani
mesh_terms: D020003:1-Octanol / Q000737:chemistry; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000081:Acetamides / Q000737:chemistry; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004285:Dogs; D004298:Dopamine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry; D015259:Dopamine Agents / Q000008:administration & dosage* / Q000737:chemistry; D042783:Endothelial Cells / Q000378:metabolism; D007980:Levodopa / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D016627:Oxidopamine; D010300:Parkinson Disease / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D020112:Rhodamine 123 / Q000378:metabolism; D014867:Water / Q000737:chemistry
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000081:Acetamides; D015259:Dopamine Agents; D011355:Prodrugs; D011963:Receptors, GABA-A; D014867:Water; D020112:Rhodamine 123; D007980:Levodopa; D016627:Oxidopamine; D020003:1-Octanol; D004298:Dopamine