title: Design and synthesis of 4-heteroaryl 1,2,3,4-tetrahydroisoquinolines as triple reuptake inhibitors.
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.
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Shuang
authors: S
authors: Liu
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Congxiang
authors: C
authors: Zha
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Kassoum
authors: K
authors: Nacro
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Min
authors: M
authors: Hu
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Wenge
authors: W
authors: Cui
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Yuh-Lin
authors: YL
authors: Yang
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Ulhas
authors: U
authors: Bhatt
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Aruna
authors: A
authors: Sambandam
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Matthew
authors: M
authors: Isherwood
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Larry
authors: L
authors: Yet
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Michael T
authors: MT
authors: Herr
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Sarah
authors: S
authors: Ebeltoft
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Carla
authors: C
authors: Hassler
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Linda
authors: L
authors: Fleming
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Anthony D
authors: AD
authors: Pechulis
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Anne
authors: A
authors: Payen-Fornicola
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Nicholas
authors: N
authors: Holman
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Dennis
authors: D
authors: Milanowski
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Ian
authors: I
authors: Cotterill
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Vadim
authors: V
authors: Mozhaev
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Yuri
authors: Y
authors: Khmelnitsky
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Peter R
authors: PR
authors: Guzzo
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Bruce J
authors: BJ
authors: Sargent
authors: AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
authors: Bruce F
authors: BF
authors: Molino
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Richard
authors: R
authors: Olson
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Dalton
authors: D
authors: King
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Snjezana
authors: S
authors: Lelas
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Yu-Wen
authors: YW
authors: Li
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Kim
authors: K
authors: Johnson
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Thaddeus
authors: T
authors: Molski
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Anitra
authors: A
authors: Orie
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Alicia
authors: A
authors: Ng
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Roy
authors: R
authors: Haskell
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Wendy
authors: W
authors: Clarke
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Robert
authors: R
authors: Bertekap
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Jonathan
authors: J
authors: O'Connell
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Nicholas
authors: N
authors: Lodge
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Michael
authors: M
authors: Sinz
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Stephen
authors: S
authors: Adams
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Robert
authors: R
authors: Zaczek
authors: Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: John E
authors: JE
authors: Macor
keywords: TRI; Triple reuptake inhibitor; antidepressant; depression; dopamine reuptake inhibitor; norepinephrine reuptake inhibitor; serotonin reuptake inhibitor