LAUSR

In our constant search for new successors of Agomelatine, we report herein another new series of compounds resulting from bio-isosteric modulation of the naphthalene ring. New 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 towards both MT 1 and MT 2 and the loss of 5HT 2C response, especially for tetrahydroisoquinoline in comparison with the parent compound. Interestingly, due to the presence of this nitrogen atom, a noticeable improvement in the pharmacokinetic properties was observed for all compounds.