Discovery of Novel Delta Opioid Receptor (DOR) Inverse Agonist and Irreversible (Non-Competitive) Antagonists

Molecules

Sixue Zhang¹  Vibha Pathak¹  Omar Moukha-Chafiq¹  Corinne E. Augelli-Szafran¹  John M. Streicher²  Parthasaradhireddy Tanguturi² 

[1] Department of Chemistry, Division of Drug Discovery, Southern Research Institute, Birmingham, AL 35205, USA;Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA;

关键词: delta opioid receptor;    inverse agonist;    irreversible antagonist;    non-competitive antagonist;    molecular pharmacology;   

DOI  :  10.3390/molecules26216693

来源: DOAJ

【 摘 要 】

The delta opioid receptor (DOR) is a crucial receptor system that regulates pain, mood, anxiety, and similar mental states. DOR agonists, such as SNC80, and DOR-neutral antagonists, such as naltrindole, have been developed to investigate the DOR in vivo and as potential therapeutics for pain and depression. However, few inverse agonists and non-competitive/irreversible antagonists have been developed, and none are widely available. This leaves a gap in our pharmacological toolbox and limits our ability to investigate the biology of this receptor. Thus, we designed and synthesized the novel compounds SRI-9342 as an irreversible antagonist and SRI-45127/SRI-45128 as inverse agonists. Then, these compounds were evaluated in vitro for their binding affinity by radioligand binding and functional activity by ³⁵S-GTPγS coupling and cAMP accumulation in cells expressing the human DOR. All three compounds demonstrated high binding affinity and selectivity at the DOR, and all three displayed their hypothesized molecular pharmacology of irreversible antagonism (SRI-9342) or inverse agonism (SRI-45127/SRI-45128). Together, these results demonstrate that we have designed new inverse agonists and irreversible antagonists of the DOR based on a novel chemical scaffold. These new compounds will provide new tools to investigate the biology of the DOR or even new potential therapeutics.

【 授权许可】

Unknown