TY - JOUR
T1 - Structure-Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter
T2 - Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability
AU - Slack, Rachel D.
AU - Ku, Therese C.
AU - Cao, Jianjing
AU - Giancola, Jolynn B.
AU - Bonifazi, Alessandro
AU - Loland, Claus J.
AU - Gadiano, Alexandra
AU - Lam, Jenny
AU - Rais, Rana
AU - Slusher, Barbara S.
AU - Coggiano, Mark
AU - Tanda, Gianluigi
AU - Newman, Amy Hauck
N1 - Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2020/3/12
Y1 - 2020/3/12
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.9b01188
DO - 10.1021/acs.jmedchem.9b01188
M3 - Article
C2 - 31661268
AN - SCOPUS:85075585677
SN - 0022-2623
VL - 63
SP - 2343
EP - 2357
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 5
ER -