N-[2-[(SUBSTITUTED MAN-8-YL)OXY]ETHYL]-4-(4-METHOXYPHENYL)BUTYLAMINES- SYNTHESIS AND WIDE-RANGE OF ANTAGONISM AT THE HUMAN 5HT(1A) RECEPTOR

A series of N-[2-[(substituted man-8-yl)oxy]ethyl]-4-(4-methoxyphenyl) butylamines was prepared and examined for their 5-HT1A receptor antago nist activity. The parent compound 3a and seven analogs bearing five k inds of substituents on the chroman ring were prepared from the corres ponding 8-hydroxychroman intermediates. Radioligand binding assays pro ved the compounds 3a-h to have high affinity for the rat hippocampal 5 -HT1A receptor with varied selectivity for adrenaline alpha(1) and dop amine D-2 receptors. Their antagonism was evaluated in a forskolin-sti mulated adenylate cyclase assay performed with CHO cells expressing th e human 5-HT1A receptor. Among the series, the C6-fluoro analog 3c sho wed both extremely potent affinity (K-i = 0.22 nM) and antagonism (EC( 50) = 13 nM) for the 5-HT1A receptor. Correlation analysis using subst ituent descriptors revealed a linear and negative correlation between molar refractivity of the C6-substituent and the binding affinity expr essed in pK(i).