RESUMEN
Novel compounds combining a 5-HT 1A moiety (3-aminochroman scaffold) and a 5-HT transporter (indole analogues) linked through a common basic nitrogen via an alkyl chain attached at the 1- or 3-position of the indole were evaluated for dual affinity at both the 5-HT reuptake site and the 5-HT 1A receptor. Compounds of most interest were found to have a 5-carbamoyl-8-fluoro-3-amino-3,4-dihydro-2 H-1-benzopyran linked to a 3-alkylindole (straight chain), more specifically substituted with a 5-fluoro (( R)-(-)- 35c), 5-cyano ((-)- 52a), or 5,7-difluoro ((-)- 52g). Several factors contributed to 5-HT 1A affinity, serotonin rat transporter affinity, and functional antagonism in vitro. Although most of our analogues showed good to excellent affinities at both targets, specific features such as cyclobutyl substitution on the basic nitrogen and stereochemistry at the 3-position of the chroman moiety seemed necessary for antagonism at the 5-HT 1A receptor. Branched linkers seemed to impart antagonism even as racemates; however, the potency of these analogues in the functional assay was not desirable enough to further pursue these compounds.
Asunto(s)
Antidepresivos/síntesis química , Antidepresivos/farmacología , Benzopiranos/síntesis química , Benzopiranos/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Antagonistas del Receptor de Serotonina 5-HT1 , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Animales , Antidepresivos/química , Benzopiranos/química , Línea Celular , Cricetinae , Reactivos de Enlaces Cruzados/química , Humanos , Estructura Molecular , Ratas , Receptor de Serotonina 5-HT1A/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
The design, synthesis, and structure-activity relationship of two novel classes of benzoxazine derivatives with dual selective serotonin reuptake inhibitors and 5-HT(1A) receptor activities are described.