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Bioorg Med Chem Lett. 2015;25(10):2060-4. doi: 10.1016/j.bmcl.2015.03.083. Epub 2015 Apr 3.

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

Author information

1
Center for Drug Discovery, RTI International, PO Box 12194, Research Triangle Park, NC 27709, United States. Electronic address: jbthomas@rti.org.
2
Center for Drug Discovery, RTI International, PO Box 12194, Research Triangle Park, NC 27709, United States.
3
Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Ave. North, Sherbrooke, QC J1H 5N4, Canada.

Abstract

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.

KEYWORDS:

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

PMID:
25881832
PMCID:
PMC4418200
DOI:
10.1016/j.bmcl.2015.03.083
[Indexed for MEDLINE]
Free PMC Article

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