The amide linker in nonpeptide neurotensin receptor ligands plays a key role in calcium signaling at the neurotensin receptor type 2

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Thomas, James B.¹  Giddings, Angela M.¹  Olepu, Srinivas¹  Wiethe, Robert W.¹  Warner, Keith R.¹  Sarret, Philippe²  Longpre, Jean-Michel²  Runyon, Scott P.¹  Gilmour, Brian P.¹ 

[1] RTI Int, Ctr Drug Discovery, Res Triangle Pk, NC 27709 USA

[2] Univ Sherbrooke, Fac Med & Hlth Sci, Dept Physiol & Pharmacol, Sherbrooke, PQ J1H 5N4, Canada

关键词: Neurotensin;    NTS2 receptor;    NTRC-660;    NTRC-739;    SR48692;    FLIPR assay;    Pain;   

DOI  :  10.1016/j.bmcl.2015.03.083

来源: Elsevier

【 摘 要 】

Compounds acting via the GPCR neurotensin receptor type 2 (NTS2) display analgesia in relevant preclinical models. The amide bond in nonpeptide NTS1 antagonists plays a central role in receptor recognition and molecular conformation. Using NTS2 FLIPR and binding assays, we found that it is also a key molecular structure for binding and calcium mobilization at NTS2. We found that reversed amides display a shift from agonist to antagonist activity and provided examples of the first competitive nonpeptide antagonists observed in the NTS2 FLIPR assay. These compounds will be valuable tools for determining the role of calcium signaling in vitro to NTS2 mediated analgesia. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

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