Studies toward the discovery of the next generation of antidepressants.: 3.: Dual 5-HT1A and serotonin transporter affinity within a class of N-aryloxyethylindolylalkylamines

N-Aryloxylethylindolealkylamines (5) having dual 5-HT transporter and 5-HT1A affinity are described. These compounds represent truncated analogues of our previously reported piperidinyl derivatives (3). Compounds in this investigation were found to have more similar affinities and functional activities for the 5-HT1A receptor and 5-HT transporter. Though 5-HT1A antagonism is not consistently observed throughout series 5, several molecular features were found to be essential to obtain high and balanced activities. The proper placement of a heteroatom in the aryl ring and the length of the linkage used to tether the indole moiety had significant influence on 5-HT1A and 5-HT transporter affinities. Introduction of a halogen into the aryl ring usually lowered intrinsic activity and in some cases led to full 5-HT1A antagonists. Compounds 33 and 34 were observed to be full 5-HT1A antagonists with K-i values of approximately 30 nM for the 5-HT1A receptor and K-i values of 5 and 0.5 nM for the 5-HT transporter, respectively. Unfortunately, similar to our previous series (3), compounds in this report also had high affinity for the alpha(1) receptor.