N-[2-[(Substituted chroman-8-yl)oxy]ethyl]-4-(4-methoxyphenyl)butylamines:  Synthesis and Wide Range of Antagonism at the Human 5-HT1A Receptor

A series of N-[2-[(substituted chroman-8-yl)oxy]ethyl]-4-(4-methoxyphenyl)butylamines was prepared and examined for their 5-HT1A receptor antagonist activity. The parent compound 3a and seven analogs bearing five kinds of substituents on the chroman ring were prepared from the corresponding 8-hydroxychroman intermediates. Radioligand binding assays proved the compounds 3a−h to have high affinity for the rat hippocampal 5-HT1A receptor with varied selectivity for adrenaline α1 and dopamine D2 receptors. Their antagonism was evaluated in a forskolin-stimulated adenylate cyclase assay performed with CHO cells expressing the human 5-HT1A receptor. Among the series, the C6-fluoro analog 3c showed both extremely potent affinity (K i = 0.22 nM) and antagonism (EC50 = 13 nM) for the 5-HT1A receptor. Correlation analysis using substituent descriptors revealed a linear and negative correlation between molar refractivity of the C6-substituent and the binding affinity expressed in pK i.