Structure-Activity Relationship Studies on a Series of 3α-[Bis(4-fluorophenyl)methoxy]tropanes and 3α-[Bis(4-fluorophenyl)methylamino]tropanes As Novel Atypical Dopamine Transporter (DAT) Inhibitors for the Treatment of Cocaine Use Disorders
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Structure-Activity Relationship Studies on a Series of 3α-[Bis(4-fluorophenyl)methoxy]tropanes and 3α-[Bis(4-fluorophenyl)methylamino]tropanes As Novel Atypical Dopamine Transporter (DAT) Inhibitors for the Treatment of Cocaine Use Disorders. / Zou, Mu Fa; Cao, Jianjing; Abramyan, Ara M.; Kopajtic, Theresa; Zanettini, Claudio; Guthrie, Daryl A.; Rais, Rana; Slusher, Barbara S.; Shi, Lei; Loland, Claus J.; Newman, Amy Hauck.
In: Journal of Medicinal Chemistry, Vol. 60, No. 24, 12.2017, p. 10172-10187.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Structure-Activity Relationship Studies on a Series of 3α-[Bis(4-fluorophenyl)methoxy]tropanes and 3α-[Bis(4-fluorophenyl)methylamino]tropanes As Novel Atypical Dopamine Transporter (DAT) Inhibitors for the Treatment of Cocaine Use Disorders
AU - Zou, Mu Fa
AU - Cao, Jianjing
AU - Abramyan, Ara M.
AU - Kopajtic, Theresa
AU - Zanettini, Claudio
AU - Guthrie, Daryl A.
AU - Rais, Rana
AU - Slusher, Barbara S.
AU - Shi, Lei
AU - Loland, Claus J.
AU - Newman, Amy Hauck
PY - 2017/12
Y1 - 2017/12
N2 - The development of medications to treat cocaine use disorders has thus far defied success, leaving this patient population without pharmacotherapeutic options. As the dopamine transporter (DAT) plays a prominent role in the reinforcing effects of cocaine that can lead to addiction, atypical DAT inhibitors have been developed that prevent cocaine from binding to DAT, but they themselves are not cocaine-like. Herein, a series of novel DAT inhibitors were synthesized, and based on its pharmacological profile, the lead compound 10a was evaluated in phase I metabolic stability studies in mouse liver microsomes and compared to cocaine in locomotor activity and drug discrimination paradigms in mice. A molecular dynamic simulation study supported the hypothesis that atypical DAT inhibitors have similar binding poses at DAT in a conformation that differs from that of cocaine. Such differences may ultimately contribute to their unique behavioral profiles and potential for development as cocaine use disorder therapeutics.
AB - The development of medications to treat cocaine use disorders has thus far defied success, leaving this patient population without pharmacotherapeutic options. As the dopamine transporter (DAT) plays a prominent role in the reinforcing effects of cocaine that can lead to addiction, atypical DAT inhibitors have been developed that prevent cocaine from binding to DAT, but they themselves are not cocaine-like. Herein, a series of novel DAT inhibitors were synthesized, and based on its pharmacological profile, the lead compound 10a was evaluated in phase I metabolic stability studies in mouse liver microsomes and compared to cocaine in locomotor activity and drug discrimination paradigms in mice. A molecular dynamic simulation study supported the hypothesis that atypical DAT inhibitors have similar binding poses at DAT in a conformation that differs from that of cocaine. Such differences may ultimately contribute to their unique behavioral profiles and potential for development as cocaine use disorder therapeutics.
U2 - 10.1021/acs.jmedchem.7b01454
DO - 10.1021/acs.jmedchem.7b01454
M3 - Journal article
C2 - 29227643
AN - SCOPUS:85040014872
VL - 60
SP - 10172
EP - 10187
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 24
ER -
ID: 196883863