TY - JOUR
T1 - Structure-activity relationships for a series of (Bis(4-fluorophenyl)methyl)sulfinylethyl-aminopiperidines and -piperidine amines at the dopamine transporter
T2 - Bioisosteric replacement of the piperazine improves metabolic stability
AU - Giancola, Jo Lynn B.
AU - Bonifazi, Alessandro
AU - Cao, Jianjing
AU - Ku, Therese
AU - Haraczy, Alexandra J.
AU - Lam, Jenny
AU - Rais, Rana
AU - Coggiano, Mark A.
AU - Tanda, Gianluigi
AU - Newman, Amy Hauck
N1 - Publisher Copyright:
© 2020 Elsevier Masson SAS
PY - 2020/12/15
Y1 - 2020/12/15
N2 - 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 Ki = 50.6 nM), 21b (DAT Ki = 77.2 nM) and 33 (DAT Ki = 30.0 nM) produced only minimal stimulation of ambulatory activity in mice, compared to cocaine, suggesting an atypical DAT inhibitor profile.
AB - 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 Ki = 50.6 nM), 21b (DAT Ki = 77.2 nM) and 33 (DAT Ki = 30.0 nM) produced only minimal stimulation of ambulatory activity in mice, compared to cocaine, suggesting an atypical DAT inhibitor profile.
KW - ASMWBPNCBDZFBV-UHFFFAOYSA-N
KW - Atypical dopamine uptake inhibitors
KW - AWFGXHAQIOOJCD-UHFFFAOYSA-N
KW - Cocaine
KW - DAT
KW - FECGZFUZXKQCAY-UHFFFAOYSA-N
KW - Modafinil
KW - NET
KW - Psychostimulant use disorders
KW - SERT
KW - Sigma receptors
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U2 - 10.1016/j.ejmech.2020.112674
DO - 10.1016/j.ejmech.2020.112674
M3 - Article
C2 - 32947229
AN - SCOPUS:85090711389
SN - 0223-5234
VL - 208
JO - European journal of medicinal chemistry
JF - European journal of medicinal chemistry
M1 - 112674
ER -