| Autor: |
Deau E; Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, CNRS, UMR 7311 , rue de Chartres, F-45067 Orleans, France., Robin E; Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique (CNRS), UPR 4301, Université d'Orléans et INSERM , rue Charles Sadron, 45071 Orléans Cedex 2, France., Voinea R; Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, CNRS, UMR 7311 , rue de Chartres, F-45067 Orleans, France.; Centrul de Cercetare 'Chimie Aplicată şi Inginerie de Proces', Universitatea din Bacău , Calea Mărăşesti, nr. 157, 600115 Bacău, Romania., Percina N; Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, CNRS, UMR 7311 , rue de Chartres, F-45067 Orleans, France., Satała G; Institute of Pharmacology, Polish Academy of Sciences , 12 Smętna Street, Kraków 31-343, Poland., Finaru AL; Centrul de Cercetare 'Chimie Aplicată şi Inginerie de Proces', Universitatea din Bacău , Calea Mărăşesti, nr. 157, 600115 Bacău, Romania., Chartier A; Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, CNRS, UMR 7311 , rue de Chartres, F-45067 Orleans, France., Tamagnan G; Molecular NeuroImaging , 60 Temple Street, New Haven, Connecticut 06510, United States., Alagille D; Molecular NeuroImaging , 60 Temple Street, New Haven, Connecticut 06510, United States., Bojarski AJ; Institute of Pharmacology, Polish Academy of Sciences , 12 Smętna Street, Kraków 31-343, Poland., Morisset-Lopez S; Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique (CNRS), UPR 4301, Université d'Orléans et INSERM , rue Charles Sadron, 45071 Orléans Cedex 2, France., Suzenet F; Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, CNRS, UMR 7311 , rue de Chartres, F-45067 Orleans, France., Guillaumet G; Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, CNRS, UMR 7311 , rue de Chartres, F-45067 Orleans, France. |
| Abstrakt: |
We report the synthesis of 46 tertiary amine-bearing N-alkylated benzo[d]imidazol-2(3H)-ones, imidazo[4,5-b]pyridin-2(3H)-ones, imidazo[4,5-c]pyridin-2(3H)-ones, benzo[d]oxazol-2(3H)-ones, oxazolo[4,5-b]pyridin-2(3H)-ones and N,N'-dialkylated benzo[d]imidazol-2(3H)-ones. These compounds were evaluated against 5-HT7R, 5-HT2AR, 5-HT1AR, and 5-HT6R as potent dual 5-HT7/5-HT2A serotonin receptors ligands. A thorough study of the structure-activity relationship of the aromatic rings and their substituents, the alkyl chain length and the tertiary amine was conducted. 1-(4-(4-(4-Fluorobenzoyl)piperidin-1-yl)butyl)-1H-benzo[d]imidazol-2(3H)-one (79) and 1-(6-(4-(4-fluorobenzoyl)piperidin-1-yl)hexyl)-1H-benzo[d]imidazol-2(3H)-one (81) were identified as full antagonist ligands on cyclic adenosine monophosphate (cAMP, KB = 4.9 and 5.9 nM, respectively) and inositol monophosphate (IP1, KB = 0.6 and 16 nM, respectively) signaling pathways of 5-HT7R and 5-HT2AR. Both antagonists crossed the blood-brain barrier as evaluated with [(18)F] radiolabeled compounds [(18)F]79 and [(18)F]81 in a primate's central nervous system using positron emission tomography. Both radioligands showed standard uptake values ranging from 0.8 to 1.1, a good plasmatic stability, and a distribution consistent with 5-HT7R and 5-HT2AR in the CNS. |
