title: The identification of nonpeptide neurotensin receptor partial agonists from the potent antagonist SR48692 using a calcium mobilization assay.
abstract: In a search for nonpeptide agonists for the neurotensin receptor (NTR1), we replaced the adamantyl amino acid moiety found in the antagonist SR48692 (1a) with leucine and related alpha-alkylamino acids found in peptide agonists. When tested in a calcium mobilization assay, we found that both d- and l-leucine confer partial agonist activity to the pyrazole scaffold with the l-enantiomer (3a) providing a significantly greater response. A brief SAR survey demonstrated that the observed agonist activity was resilient to changes made to the dimethoxyaryl ring in 3a. The resulting compounds were less potent relative to 3a but showed greater agonist responses. The partial agonist activity was extinguished when the chloroquinoline ring was replaced with naphthalene. Thus, while l-leucine appears to possess a powerful agonist directing affect for the NTR1 receptor, its presence alone in the molecular architecture is not sufficient to insure agonist behavior.
authors.affiliation: Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Thomas
authors.forename: Hernán
authors.initials: H
authors.lastname: Navarro
authors.forename: Keith R
authors.initials: KR
authors.lastname: Warner
authors.forename: Brian
authors.initials: B
authors.lastname: Gilmour
mesh_terms: D000818:Animals; D016466:CHO Cells; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D011485:Protein Binding / Q000502:physiology; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D018028:Receptors, Neurotensin / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D011720:Pyrazoles; D011804:Quinolines; D018028:Receptors, Neurotensin; C079087:SR 48692