Pharma / Biotech

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.

Related Articles

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.

J Med Chem. 2019 Oct 29;:

Authors: Slack RD, Ku T, Cao J, Giancola J, Bonifazi A, Loland CJ, Gadiano A, Lam J, Rais R, Slusher BS, Coggiano M, Tanda G, Newman AH

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 sigma1 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.

PMID: 31661268 [PubMed – as supplied by publisher]

Source link

Related posts

LEVAQUIN (Levofloxacin) Tablet, Film Coated [Janssen Pharmaceuticals, Inc.]

Newsemia

Pharmacogenetics of Antiretroviral Drug Response and Pharmacokinetic Variations in Indigenous South African Populations.

Newsemia

CMS a Powerful Agent of Change for ABx Stewardship

Newsemia

This website uses cookies to improve your experience. We'll assume you're ok with this, but you can opt-out if you wish. Accept Read More

Privacy & Cookies Policy

COVID-19

COVID-19 (Coronavirus) is a new illness that is having a major effect on all businesses globally LIVE COVID-19 STATISTICS FOR World