title: The amide linker in nonpeptide neurotensin receptor ligands plays a key role in calcium signaling at the neurotensin receptor type 2.
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.
authors.affiliation: Center for Drug Discovery, RTI International, PO Box 12194, Research Triangle Park, NC 27709, United States. Electronic address: jbthomas@rti.org.
authors.forename: James B
authors.initials: JB
authors.lastname: Thomas
authors.affiliation: Center for Drug Discovery, RTI International, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Giddings
authors.affiliation: Center for Drug Discovery, RTI International, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Olepu
authors.affiliation: Center for Drug Discovery, RTI International, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wiethe
authors.affiliation: Center for Drug Discovery, RTI International, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Warner
authors.affiliation: Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Ave. North, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarret
authors.affiliation: Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Ave. North, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Longpre
authors.affiliation: Center for Drug Discovery, RTI International, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Runyon
authors.affiliation: Center for Drug Discovery, RTI International, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Gilmour
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001681:Biological Assay; D020013:Calcium Signaling / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy; D011485:Protein Binding / Q000187:drug effects; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000577:Amides; D008024:Ligands; D018028:Receptors, Neurotensin
keywords: FLIPR assay; NTRC-660; NTRC-739; NTS2 receptor; Neurotensin; Pain; SR48692