title: Identification of 2-({[1-(4-Fluorophenyl)-5-(2-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}amino)tricyclo[3.3.1.13,7]decane-2-carboxylic Acid (NTRC-844) as a Selective Antagonist for the Rat Neurotensin Receptor Type 2.
abstract: Neurotensin receptor type 2 (NTS2) compounds display analgesic activity in animal pain models. We have identified the first high-affinity NTS2-selective antagonist (8) that is active in vivo. This study also revealed that the NTS2 FLIPR assay designation for a compound, agonist, partial agonist, and so forth, did not correlate with its in vivo activity as observed in the thermal tail-flick acute model of pain. This suggests that calcium mobilization is not the signaling pathway involved in NTS2-mediated analgesia as assessed by the thermal tail-flick model. Finally, we found a significant bias between rat and human for compound 9 in the NTS2 binding assay.
authors.affiliation: Center for Drug Discovery, RTI International , P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States.
authors.forename: James B
authors.initials: JB
authors.lastname: Thomas
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: Mélanie
authors.initials: M
authors.lastname: Vivancos
authors.affiliation: Center for Drug Discovery, RTI International , P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Giddings
authors.affiliation: Center for Drug Discovery, RTI International , P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wiethe
authors.affiliation: Center for Drug Discovery, RTI International , P.O. Box 12194, Research Triangle Park, North Carolina 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: Alexandre
authors.initials: A
authors.lastname: Murza
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: Élie
authors.initials: É
authors.lastname: Besserer-Offroy
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: Longpré
authors.affiliation: Center for Drug Discovery, RTI International , P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Runyon
authors.affiliation: Center for Drug Discovery, RTI International , P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Decker
authors.affiliation: Center for Drug Discovery, RTI International , P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Gilmour
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
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D002264:Carboxylic Acids / Q000737:chemistry*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019417:Hindlimb Suspension; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D018377:Neurotransmitter Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D010880:Piperidines / Q000737:chemistry*; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002264:Carboxylic Acids; C000624247:NTRC-844; D018377:Neurotransmitter Agents; D010880:Piperidines; D011720:Pyrazoles; D018028:Receptors, Neurotensin; D002118:Calcium
keywords: FLIPR assay; NT79; NTRC-844; NTS2 receptor; Neurotensin; analgesia; thermal tail-flick