Structure-activity relationships for a series of (Bis(4-fluorophenyl)methyl)sulfinylethyl-aminopiperidines and -piperidine amines at the dopamine transporter: Bioisosteric replacement of the piperazine improves metabolic stability

Abstract

Despite considerable efforts to develop medications to treat psychostimulant use disorders, none have proven effective, leaving an underserved patient population and unanswered questions as to what mechanism(s) of action should be targeted for developing pharmacotherapies. Atypical dopamine transporter (DAT) inhibitors, based on (±)modafinil, have shown therapeutic potential in preclinical models of psychostimulant abuse. However, metabolic instability among other limitations to piperazine analogues 1-3 have impeded further development. Herein, bioisosteric substitutions of the piperazine ring were explored with a series of aminopiperidines (A) and piperidine amines (B) wherein compounds with either a terminal tertiary amine or amide were synthesized. Several lead compounds showed high to moderate DAT affinities and metabolic stability in rat liver microsomes. Aminopiperidines 7 (DAT K_i = 50.6 nM), 21b (DAT K_i = 77.2 nM) and 33 (DAT K_i = 30.0 nM) produced only minimal stimulation of ambulatory activity in mice, compared to cocaine, suggesting an atypical DAT inhibitor profile.

Keywords: Atypical dopamine uptake inhibitors; Cocaine; DAT; Modafinil; NET; Psychostimulant use disorders; SERT; Sigma receptors.