title: Identification of N-{[6-chloro-4-(2,6-dimethoxyphenyl)quinazolin-2-yl]carbonyl}-l-leucine (NTRC-808), a novel nonpeptide chemotype selective for the neurotensin receptor type 2.
abstract: Compounds acting via the GPCR neurotensin receptor type 2 (NTS2) display analgesic effects in relevant animal models. Using a pharmacophore model based on known NT receptor nonpeptide compounds, we screened commercial databases to identify compounds that might possess activity at NTS2 receptor sites. Modification of our screening hit to include structural features known to be recognized by NTS1 and NTS2, led to the identification of the novel NTS2 selective nonpeptide, N-{[6-chloro-4-(2,6-dimethoxyphenyl)quinazolin-2-yl]carbonyl}-l-leucine (9). This compound is a potent partial agonist in the FLIPR assay with a profile of activity similar to that of the reference NTS2 analgesic nonpeptide levocabastine (5).
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute, 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 Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Giddings
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Olepu
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wiethe
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Danni L
authors.initials: DL
authors.lastname: Harris
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Sanju
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Warner
authors.affiliation: Department of Physiology and Biophysics, 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 Physiology and Biophysics, 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 Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Runyon
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709, United States.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Gilmour
mesh_terms: D002118:Calcium / Q000378:metabolism; D054333:Drug Partial Agonism; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D018028:Receptors, Neurotensin / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C000601363:NTRC-808; C490985:NTSR2 protein, human; D011799:Quinazolines; D018028:Receptors, Neurotensin; D007930:Leucine; D002118:Calcium
keywords: FLIPR assay; Levocabastine; NTS2 receptor; Neurotensin; Pain; SR142948a; SR48692