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Synthesis and SAR Studies of Isoquinoline and Tetrahydroisoquinoline Derivatives as Melatonin Receptor Ligands
Authors:Dr. Mohamed Ettaoussi  Amélie Laversin  Brandon Vreulz  Dr. Marouane Rami  Dr. Nicolas Lebegue  Dr. Philippe Delagrange  Dr. Daniel Henri Caignard  Prof. Patricia Melnyk  Dr. Maxime Liberelle  Dr. Saïd Yous
Affiliation:1. UMR−S 1172-LiNC-Lille Neuroscience & Cognition, Univ. Lille, Inserm, CHU Lille, 59000 Lille, France;2. PEX Biotechnologie Chimie & Biologie, Institut de Recherches Servier, 78290 Croissy sur Seine, France
Abstract:In our constant search for new successors of agomelatine, we report herein a new series of compounds resulting from bioisosteric modulation of the naphthalene ring. The isoquinoline and tetrahydroisoquinoline derivatives were synthesized and pharmacologically evaluated. This isosteric replacement of the naphthalene group of agomelatine has led to potent agonist and partial agonist compounds with nanomolar melatonergic binding affinities. Overall, the presence of a nitrogen atom was accompanied with a decrease in the binding affinity toward both MT1 and MT2 and the loss of 5HT2C response, especially for tetrahydroisoquinoline in comparison with the parent compound. Interestingly, due to the presence of this nitrogen atom, a notable improvement in the pharmacokinetic properties was observed for all compounds.
Keywords:agomelatine  melatonin  MT1/MT2  isoquinoline  tetrahydroisoquinoline
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