title: Synthesis, radiosynthesis and biological evaluation of 1,4-dihydroquinoline derivatives as new carriers for specific brain delivery.
abstract: In spite of numerous reports dealing with the use of 1,4-dihydropyridines as carriers to deliver biological active compounds to the brain, this chemical delivery system (CDS) suffers from poor stability of the 1,4-dihydropyridine derivatives towards oxidation and hydration reactions seriously limiting further investigations in vivo. In an attempt to overcome these limitations, we report herein the first biological evaluation of more stable annellated NADH models in the quinoline series as relevant neuroactive drug-carrier candidates. The radiolabeled 1,4-dihydroquinoline [(11)C] was prepared to be subsequently peripherally injected in rats. The injected animals were sacrificed and brains were collected. The radioactivity measured in rat brain indicated a rapid penetration of the carrier [(11)C] into the CNS. HPLC analysis of brain homogenates showed that oxidation of [(11)C] into the corresponding quinolinium salt [(11)C] was completed in less than 5 min. An in vivo evaluation in mice is also reported to illustrate the potential of such 1,4-dihydroquinoline derivatives to transport a neuroactive drug in the CNS. For this purpose, gamma-aminobutyric acid (GABA), well known to poorly cross the brain blood barrier (BBB) was connected to this 1,4-dihydroquinoline-type carrier. After i.p. injection of 1,4-dihydroquinoline-GABA derivative in mice, a significant alteration of locomotor activity (LMA) was observed presumably resulting from an enhancement of central GABAergic activity. These encouraging results give strong evidence for the capacity of carrier-GABA derivative to cross the BBB and exert a pharmacological effect on the CNS. This study paves the way for further progress in designing new redox chemical delivery systems.
authors.affiliation: Laboratoire de Chimie Organique Fine et Hétérocyclique, UMR 6014, IRCOF, CNRS, Université et INSA de Rouen, B.P. 08 F-76131, Mont-Saint-Aignan Cedex, France.
authors.forename: Lénaïg
authors.initials: L
authors.lastname: Foucout
authors.forename: Fabienne
authors.initials: F
authors.lastname: Gourand
authors.forename: Martine
authors.initials: M
authors.lastname: Dhilly
authors.forename: Pierre
authors.initials: P
authors.lastname: Bohn
authors.forename: Georges
authors.initials: G
authors.lastname: Dupas
authors.forename: Jean
authors.initials: J
authors.lastname: Costentin
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abbas
authors.forename: Francis
authors.initials: F
authors.lastname: Marsais
authors.forename: Louisa
authors.initials: L
authors.lastname: Barré
authors.forename: Vincent
authors.initials: V
authors.lastname: Levacher
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009243:NAD / Q000737:chemistry; D010084:Oxidation-Reduction; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D011854:Radiochemistry; D051381:Rats; D005680:gamma-Aminobutyric Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: C544515:1,4-dihydroquinoline; D002250:Carbon Radioisotopes; D004337:Drug Carriers; D011804:Quinolines; D009243:NAD; D005680:gamma-Aminobutyric Acid