title: Identification of 1-({[1-(4-fluorophenyl)-5-(2-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}amino)cyclohexane carboxylic acid as a selective nonpeptide neurotensin receptor type 2 compound.
abstract: Compounds active at neurotensin receptors (NTS1 and NTS2) exert analgesic effects on different types of nociceptive modalities, including thermal, mechanical, and chemical stimuli. The NTS2 preferring peptide JMV-431 (2) and the NTS2 selective nonpeptide compound levocabastine (6) have been shown to be effective in relieving the pain associated with peripheral neuropathies. With the aim of identifying novel nonpeptide compounds selective for NTS2, we examined analogues of SR48692 (5a) using a FLIPR calcium assay in CHO cells stably expressing rat NTS2. This led to the discovery of the NTS2 selective nonpeptide compound 1-({[1-(4-fluorophenyl)-5-(2-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}amino)cyclohexane carboxylic acid (NTRC-739, 7b) starting from the nonselective compound 5a.
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States.
authors.forename: James B
authors.initials: JB
authors.lastname: Thomas
authors.forename: Angela M
authors.initials: AM
authors.lastname: Giddings
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wiethe
authors.forename: Srinivas
authors.initials: S
authors.lastname: Olepu
authors.forename: Keith R
authors.initials: KR
authors.lastname: Warner
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarret
authors.forename: Louis
authors.initials: L
authors.lastname: Gendron
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Longpre
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Scott P
authors.initials: SP
authors.lastname: Runyon
authors.forename: Brian P
authors.initials: BP
authors.lastname: Gilmour
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D003412:Cricetulus; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054333:Drug Partial Agonism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018028:Receptors, Neurotensin / Q000819:agonists* / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: C000591351:1-(((1-(4-fluorophenyl)-5-(2-methoxyphenyl)-1H-pyrazol-3-yl)carbonyl)amino)cyclohexanecarboxylic acid; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; C099727:Ntsr2 protein, rat; D011720:Pyrazoles; D018028:Receptors, Neurotensin; D002118:Calcium