| Literature DB >> 25050161 |
Shuang Liu1, Congxiang Zha1, Kassoum Nacro1, Min Hu1, Wenge Cui1, Yuh-Lin Yang1, Ulhas Bhatt1, Aruna Sambandam1, Matthew Isherwood1, Larry Yet1, Michael T Herr1, Sarah Ebeltoft1, Carla Hassler1, Linda Fleming1, Anthony D Pechulis1, Anne Payen-Fornicola1, Nicholas Holman1, Dennis Milanowski1, Ian Cotterill1, Vadim Mozhaev1, Yuri Khmelnitsky1, Peter R Guzzo1, Bruce J Sargent1, Bruce F Molino1, Richard Olson2, Dalton King2, Snjezana Lelas2, Yu-Wen Li2, Kim Johnson2, Thaddeus Molski2, Anitra Orie2, Alicia Ng2, Roy Haskell2, Wendy Clarke2, Robert Bertekap2, Jonathan O'Connell2, Nicholas Lodge2, Michael Sinz2, Stephen Adams2, Robert Zaczek2, John E Macor2.
Abstract
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.Entities:
Keywords: TRI; Triple reuptake inhibitor; antidepressant; depression; dopamine reuptake inhibitor; norepinephrine reuptake inhibitor; serotonin reuptake inhibitor
Year: 2014 PMID： 25050161 PMCID： PMC4094255 DOI： 10.1021/ml500053b
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345