We report the synthesis of a new set of compounds of general structure I (1-20) with structural modifications in the pharmacophoric elements of the previously reported lead UCM-5600. The new derivatives have been evaluated for binding affinity at 5-HT7 and 5-HT1A receptors. The influence of the different structural features in terms of 5-HT 7/5-HT1A receptor affinity and selectivity was analyzed by computational simulations of the complexes between compounds I and β2-based 3-D models of these receptors. Compound 18 (HYD 1) 1,3-dihydro-2H-indol-2-one; spacer) -(CH2)4-; HYD 2 + HYD3 3,4-dihydroisoquinolin-2(1 H)-yl) exhibits high 5-HT7R affinity (Ki) 7 nM) and selectivity over the 5-HT1AR (31-fold), and has been characterized as a partial agonist of the human 5-HT7R. © 2009 American Chemical Society.
|Journal||Journal of Medicinal Chemistry|
|Publication status||Published - 23 Apr 2009|
Medina, R. A., Sallander, J., Benhamú, B., Porras, E., Campillo, M., Pardo, L., & López-Rodríguez, M. L. (2009). Synthesis of new serotonin 5-HT<inf>7</inf> receptor ligands. Determinants of 5-ht7/5-ht<inf>1a</inf> receptor selectivity. Journal of Medicinal Chemistry, 52, 2384-2392. https://doi.org/10.1021/jm8014553