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|