New tetrahydroisoquinoline-based D3R ligands with an o-xylenyl linker motif

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:42

Article

Cordone, Pierpaolo^1,2  Namballa, Hari K.¹  Muniz, Bryant¹  Pal, Rajat K.^2,4  Gallicchio, Emilio^2,3,4  Harding, Wayne W.^1,2,3 

[1] CUNY Hunter Coll, Dept Chem, 695 Pk Ave, New York, NY 10065 USA

[2] CUNY, Grad Ctr, Program Biochem, 365 5th Ave, New York, NY 10016 USA

[3] CUNY, Grad Ctr, Program Chem, 365 5th Ave, New York, NY 10016 USA

[4] Brooklyn Coll, Dept Chem, 2900 Bedford Ave, Brooklyn, NY 11210 USA

关键词: Tetrahydroisoquinoline;    Dopamine receptor;    D3R;    sigma R-2;    Docking;   

DOI  :  10.1016/j.bmcl.2021.128047

来源: Elsevier

【 摘 要 】

The effect of rigidification of the n-butyl linker region of tetrahydroisoquinoline-containing D3R ligands via inclusion of an o-xylenyl motif was examined in this study. Generally, rigidification with an o-xylenyl linker group reduces D3R affinity and negatively impacts selectivity versus D2R for compounds possessing a 6-methoxy1,2,3,4,-tetrahydroisoquinolin-7-ol primary pharmacophore group. However, D3R affinity appears to be regulated by the primary pharmacophore group and high affinity D3R ligands with 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline primary pharmacophore groups were identified. The results of this study also indicate that D3R selectivity versus the sigma R-2 is dictated by the benzamide secondary pharmacophore group, this being facilitated with 4-substituted benzamides. Compounds 5s and 5t were identified as high affinity (Ki < 4 nM) D3R ligands. Docking studies revealed that the added phenyl ring moiety interacts with the Cys181 in D3R which partially accounts for the strong D3R affinity of the ligands.

【 授权许可】

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