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

Rachel D. Slack, Therese C. Ku, Jianjing Cao, Jo Lynn B. Giancola, Alessandro Bonifazi, Claus J. Loland, Alexandra Gadiano, Jenny Lam, Rana Rais, Barbara S. Slusher, Mark Coggiano, Gianluigi Tanda, Amy Hauck Newman

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalJournal of medicinal chemistry
DOIs
StateAccepted/In press - Jan 1 2019

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Dopamine Plasma Membrane Transport Proteins
Structure-Activity Relationship
Amines
Nitrogen
Cocaine
Serotonin Plasma Membrane Transport Proteins
2-Propanol
Methamphetamine
Liver Microsomes
Locomotion
Pharmacokinetics
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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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. / Slack, Rachel D.; Ku, Therese C.; Cao, Jianjing; Giancola, Jo Lynn B.; Bonifazi, Alessandro; Loland, Claus J.; Gadiano, Alexandra; Lam, Jenny; Rais, Rana; Slusher, Barbara S.; Coggiano, Mark; Tanda, Gianluigi; Newman, Amy Hauck.

In: Journal of medicinal chemistry, 01.01.2019.

Research output: Contribution to journalArticle

Slack, Rachel D. ; Ku, Therese C. ; Cao, Jianjing ; Giancola, Jo Lynn B. ; Bonifazi, Alessandro ; Loland, Claus J. ; Gadiano, Alexandra ; Lam, Jenny ; Rais, Rana ; Slusher, Barbara S. ; Coggiano, Mark ; Tanda, Gianluigi ; Newman, Amy Hauck. / 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. In: Journal of medicinal chemistry. 2019.
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abstract = "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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