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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.

SUBMITTER: Liu S

PROVIDER: S-EPMC4094255 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Design and synthesis of 4-heteroaryl 1,2,3,4-tetrahydroisoquinolines as triple reuptake inhibitors.

Liu Shuang S Zha Congxiang C Nacro Kassoum K Hu Min M Cui Wenge W Yang Yuh-Lin YL Bhatt Ulhas U Sambandam Aruna A Isherwood Matthew M Yet Larry L Herr Michael T MT Ebeltoft Sarah S Hassler Carla C Fleming Linda L Pechulis Anthony D AD Payen-Fornicola Anne A Holman Nicholas N Milanowski Dennis D Cotterill Ian I Mozhaev Vadim V Khmelnitsky Yuri Y Guzzo Peter R PR Sargent Bruce J BJ Molino Bruce F BF Olson Richard R King Dalton D Lelas Snjezana S Li Yu-Wen YW Johnson Kim K Molski Thaddeus T Orie Anitra A Ng Alicia A Haskell Roy R Clarke Wendy W Bertekap Robert R O'Connell Jonathan J Lodge Nicholas N Sinz Michael M Adams Stephen S Zaczek Robert R Macor John E JE

ACS medicinal chemistry letters 20140513 7

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 ...[more]

PMID: 25050161

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Project description:BackgroundAcquired Immune Deficiency Syndrome (AIDS) is the advanced stage of infection caused by Human Immunodeficiency Virus (HIV). HIV/AIDS had a great impact on society, both as an illness and as a source of discrimination. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are structurally diverse group of compounds which binds to Reverse Transcriptase (RT) enzyme of HIV. Like other anti-HIV drugs, long-term clinical effectiveness of approved NNRTIs has been hampered due to the rapid development of drug resistance. So, there is an urgent need to discover the NNRTIs, which can be effective against the drug sensitive as well as drug resistant strains of HIV-1 RT.ResultsTwo series of novel thirty, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline analogues (5a-o) and (8a-o) were designed and synthesized as inhibitor of HIV-1 reverse transcriptase. All the synthesized compounds were characterized by infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, mass spectroscopy and evaluated for in-vitro RT inhibitory activity. Among the tested compounds, eighteen compounds exhibited more than 50 % inhibition at tested 100 μM concentration, in which two compounds 8h and 8l showed promising inhibition (74.82 and 72.58 %) respectively. The preliminary structure-activity relationship (SAR) of the test compounds and docking studies of the two significantly active compounds 8h and 8l were performed to examine their putative binding with HIV-RT. Predicted physiochemical parameters of the synthesized compounds were within the acceptable range of drugable properties.ConclusionThe results obtained from this investigation revealed that, the synthesized compounds (5a-o) and (8a-o) showed moderate to promising HIV-1 RT inhibition activity. The overall SAR studies can help in identification of further lead as well as in designing of newer potential inhibitor of HIV-1 RT. Graphical AbstractBest docked pose of compound 8h inside the non-nucleoside inhibitory binding pocket of 3MEE enzyme.

Dataset Information

Design and synthesis of 4-heteroaryl 1,2,3,4-tetrahydroisoquinolines as triple reuptake inhibitors.

Publications

Design and synthesis of 4-heteroaryl 1,2,3,4-tetrahydroisoquinolines as triple reuptake inhibitors.

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