Design, synthesis and biological evaluation of new classes of serotoninergic 5-HT7 ligands ; Conception, synthèse et évaluation biologique de nouvelles classes de ligands sérotoninergiques 5-HT7

Among all the neurotransmitters identified up-to-date, serotonin (5-Hydroxytryptamine, 5-HT) is mediated by the most complex system of receptors. The 5-HT7 receptors are the latest discovered (1993) and have many implications both in the central nervous system and in peripheral tissues. The therapeutic potential of new 5- HT7 ligands, selective over the other GPCRs, motivated our research project. Our studies were focused on the design of three different classes of 5-HT7 ligands. The first class was built on a benzimidazolone scaffold. Various modulations afforded a shift of the affinity profile from the 5-HT1ARs to the 5-HT7Rs. A second class of 3-aminofuro- or pyrano[2,3-b]pyridines are in fact the heteroanalogues of one of the most interesting current 5-HT7 selective agonists: the 3-aminochromans. Their synthesis involved an intramolecular Diels-Alder cycloaddition key step starting from a 1,2,4-triazine judiciously substituted in 3 with a convenient aminoalkynol. The developed methodology afforded the variation of the substituents on the amine moiety, of the aromatic substituent and its position on the pyridinic core and of the non-aromatic ring size. A last class of bisarylic derivatives further explored the SAR tendencies of this type of 5-HT7 ligands by modulating the main aromatic scaffold in the benzene, pyrimidine and 1,2,4-triazine series. ; Parmi tous les neurotransmetteurs identifiés à ce jour, la sérotonine (5-hydroxytryptamine, 5-HT) est impliquée dans le système le plus complexe de récepteurs. Parmi eux, les récepteurs 5-HT7 qui sont les derniers découverts (1993) semblent avoir des implications multiples tant au niveau central que périphérique. Le potentiel thérapeutique représenté par la découverte de ligands 5-HT7 sélectifs vis-à-vis d’autres RCPGs a motivé notre projet de recherche. Nos études sont orientées vers la conception de trois classes distinctes de ligands. Une première famille à été conçue sur une charpente benzimidazolone. Diverses pharmacomodulations ont permis un changement du ...