The identification of nonpeptide neurotensin receptor partial agonists from the potent antagonist SR48692 using a calcium mobilization assay

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:19

Article

Thomas, James B.¹  Navarro, Hernan¹  Warner, Keith R.¹  Gilmour, Brian¹ 

[1] Res Triangle Inst, Res Triangle Pk, NC 27709 USA

关键词: Neurotensin;    Partial agonist;    Antagonist;    Nonpeptide;   

DOI  :  10.1016/j.bmcl.2009.01.024

来源: Elsevier

【 摘 要 】

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. (C) 2009 Elsevier Ltd. All rights reserved.

【 授权许可】

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