title: Synthesis of new serotonin 5-HT7 receptor ligands. Determinants of 5-HT7/5-HT1A receptor selectivity.
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-HT(7) and 5-HT(1A) receptors. The influence of the different structural features in terms of 5-HT(7)/5-HT(1A) receptor affinity and selectivity was analyzed by computational simulations of the complexes between compounds I and beta(2)-based 3-D models of these receptors. Compound 18 (HYD(1) = 1,3-dihydro-2H-indol-2-one; spacer = -(CH(2))(4)-; HYD(2) + HYD(3) = 3,4-dihydroisoquinolin-2(1H)-yl) exhibits high 5-HT(7)R affinity (K(i) = 7 nM) and selectivity over the 5-HT(1A)R (31-fold), and has been characterized as a partial agonist of the human 5-HT(7)R.
authors.affiliation: Departamento de Quimica Organica I, Facultad de Ciencias Quimicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Rocío A
authors.initials: RA
authors.lastname: Medina
authors.forename: Jessica
authors.initials: J
authors.lastname: Sallander
authors.forename: Bellinda
authors.initials: B
authors.lastname: Benhamú
authors.forename: Esther
authors.initials: E
authors.lastname: Porras
authors.forename: Mercedes
authors.initials: M
authors.lastname: Campillo
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pardo
authors.forename: María L
authors.initials: ML
authors.lastname: López-Rodríguez