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Synthesis of New Serotonin 5-HT 7 Receptor Ligands. Determinants of 5-HT 7 /5-HT 1A Receptor Selectivity

2009; American Chemical Society; Volume: 52; Issue: 8 Linguagem: Inglês

10.1021/jm8014553

1520-4804

Rocío A. Medina, Jessica Sallander, Bellinda Benhamú, Esther Porras, Mercedes Campillo, Leonardo Pardo, María L. López-Rodrı́guez,

Chemical synthesis and alkaloids

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-HT7/5-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 (HYD1 = 1,3-dihydro-2H-indol-2-one; spacer = −(CH2)4−; HYD2 + HYD3 = 3,4-dihydroisoquinolin-2(1H)-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.