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

Journal of Medicinal Chemistry
Richard E MewshawTerrance H Andree

Abstract

N-aryloxylethylindolealkylamines (5) having dual 5-HT transporter and 5-HT(1A) 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-HT(1A) receptor and 5-HT transporter. Though 5-HT(1A) 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-HT(1A) 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-HT(1A) antagonists. Compounds 33 and 34 were observed to be full 5-HT(1A) antagonists with K(i) values of approximately 30 nM for the 5-HT(1A) 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.

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Citations

Mar 5, 2005·Bioorganic & Medicinal Chemistry Letters·William D SchmitzJohn E Macor
Feb 21, 2006·NeuroRx : the Journal of the American Society for Experimental NeuroTherapeutics·Lee E SchechterSharon Rosenzweig-Lipson
May 11, 2017·Journal of Medicinal Chemistry·Barbara MännelPeter Gmeiner
Dec 18, 2013·Archiv der Pharmazie·Claudia Ojeda-GómezClaudio Méndez-Rojas
Jul 14, 2012·Expert Opinion on Therapeutic Patents·Enza LacivitaMarcello Leopoldo
Aug 20, 2016·Drug Development Research·Andrea MilelliCarmela Fimognari
Sep 22, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Le WangFeng Liu
Jan 23, 2021·RSC Medicinal Chemistry·Nicole McNamaraJonathan Baell
Feb 16, 2007·Journal of Medicinal Chemistry·Stephane CuisiatBernard Vacher
Oct 14, 2005·Journal of Medicinal Chemistry·Richard Morphy, Zoran Rankovic
Jan 21, 2012·Organic Letters·Nicolas GigantIsabelle Gillaizeau
Oct 23, 2018·ACS Medicinal Chemistry Letters·Caroline Chandra TjinJonathan A Ellman

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