Structure–Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter: Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability

Atypical dopamine transporter (DAT) inhibitors have shown
therapeutic
potential in preclinical models of psychostimulant abuse. In rats,
1-(4-(2-((bis­(4-fluorophenyl)­methyl)­sulfinyl)­ethyl)-piperazin-1-yl)-propan-2-ol
(3b) was effective in reducing the reinforcing effects
of both cocaine and methamphetamine but did not exhibit psychostimulant
behaviors itself. While further development of 3b is
ongoing, diastereomeric separation, as well as improvements in potency
and pharmacokinetics were desirable for discovering pipeline drug
candidates. Thus, a series of bis­(4-fluorophenyl)­methyl)­sulfinyl)­alkyl
alicyclic amines, where the piperazine-2-propanol scaffold was modified,
were designed, synthesized, and evaluated for binding affinities at
DAT, as well as the serotonin transporter and σ1 receptors.
Within the series, 14a showed improved DAT affinity (Ki = 23 nM) over 3b (Ki = 230 nM), moderate metabolic stability in human liver
microsomes, and a hERG/DAT affinity ratio = 28. While 14a increased locomotor activity relative to vehicle, it was significantly
lower than activity produced by cocaine. These results support further
investigation of 14a as a potential treatment for psychostimulant
use disorders.