Abstract
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.
Original language | English |
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Pages (from-to) | 2384-2392 |
Journal | Journal of Medicinal Chemistry |
Volume | 52 |
DOIs | |
Publication status | Published - 23 Apr 2009 |