Design and Synthesis of 4-Heteroaryl 1,2,3,4-Tetrahydroisoquinolines as Triple Reuptake Inhibitors

被引：17

作者：

Liu, Shuang ^{[1
]}

Zha, Congxiang ^{[1
]}

Nacro, Kassoum ^{[1
]}

Hu, Min ^{[1
]}

Cui, Wenge ^{[1
]}

Yang, Yuh-Lin ^{[1
]}

Bhatt, Ulhas ^{[1
]}

Sambandam, Aruna ^{[1
]}

Isherwood, Matthew ^{[1
]}

Yet, Larry ^{[1
]}

Herr, Michael T. ^{[1
]}

Ebeltoft, Sarah ^{[1
]}

Hassler, Carla ^{[1
]}

Fleming, Linda ^{[1
]}

Pechulis, Anthony D. ^{[1
]}

Payen-Fornicola, Anne ^{[1
]}

Holman, Nicholas ^{[1
]}

Milanowski, Dennis ^{[1
]}

Cotterill, Ian ^{[1
]}

Mozhaev, Vadim ^{[1
]}

Khmelnitsky, Yuri ^{[1
]}

Guzzo, Peter R. ^{[1
]}

Sargent, Bruce J. ^{[1
]}

Molino, Bruce F. ^{[1
]}

Olson, Richard ^{[2
]}

King, Dalton ^{[2
]}

Lelas, Snjezana ^{[2
]}

Li, Yu-Wen ^{[2
]}

Johnson, Kim ^{[2
]}

Molski, Thaddeus ^{[2
]}

One, Anitra ^{[2
]}

Ng, Alicia ^{[2
]}

Haskell, Roy ^{[2
]}

Clarke, Wendy ^{[2
]}

Bertekap, Robert ^{[2
]}

O'Connell, Jonathan ^{[2
]}

Lodge, Nicholas ^{[2
]}

Sinz, Michael ^{[2
]}

Adams, Stephen ^{[2
]}

Zaczek, Robert ^{[2
]}

Macor, John E. ^{[2
]}

机构：

[1] AMRI, Albany, NY 12212 USA

[2] Bristol Myers Squibb R&D, Wallingford, CT 06492 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2014年 / 5卷 / 07期

关键词：

Triple reuptake inhibitor; TRI; serotonin reuptake inhibitor; dopamine reuptake inhibitor; norepinephrine reuptake inhibitor; depression; antidepressant; DOPAMINE; NOREPINEPHRINE; DEPRESSION; OCCUPANCY; MECHANISM; SSRIS;

D O I：

10.1021/ml500053b

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure-activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (po), respectively. At efficacious doses in these assays, 10i exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of 10i revealed the formation of a significant active metabolite, compound 13.

引用

页码：760 / 765

页数：6

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