Faculty Collaboration Database

ARD-353 [4-((2R,5S)-4-(R)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-1-ylmethyl)benzoic acid], a novel nonpeptide delta receptor agonist, reduces myocardial infarct size without central effects. J Pharmacol Exp Ther 2006 Jan;316(1):423-30

Date

09/29/2005

Pubmed ID

16188952

DOI

10.1124/jpet.105.092742

Scopus ID

2-s2.0-29244490897 (requires institutional sign-in at Scopus site)   25 Citations

Abstract

A novel delta-receptor selective compound, ARD-353 [4-((2R,5S)-4-(R)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2, 5-dimethylpiperazin-1-ylmethyl)benzoic acid], was evaluated for activity on infarct size in a rat model of acute myocardial infarction. ARD-353 was characterized as having delta receptor selectivity using radioligand binding and had no apparent selectivity between delta receptor subtypes as determined by [(3)H] cyclic [D-Pen(2),D-Pen(5)]enkephalin (delta(1)) and [(3)H]Deltorphin II (delta(2)) competition binding. ARD-353 also showed selective delta receptor agonist activity in mouse-isolated vas deferens. There was no evidence of any seizure-like convulsions when ARD-353 was administered to mice either i.v. or p.o., implying minimal penetration of the blood-brain barrier. ARD-353 decreased infarct size in a left anterior descending coronary artery (LAD) occlusion model of myocardial infarction. In animals pretreated with ARD-353 (i.v.) and then subjected to 30 min of LAD occlusion followed by 90 min of reperfusion, infarct size was reduced in a dose-dependent manner compared with vehicle-treated controls. The effects of ARD-353 on infarct size were blocked by the delta(1)-opioid selective antagonist 7-benzylidenenaltrexone, indicating a significant role for the delta(1)-opioid receptor in the cardioprotective mechanism of ARD-353. ARD-353 (0.3 mg/kg i.v.) produced significant protection when administered 5 min and 12 and 48 h before ischemic insult or when given immediately after the ischemic insult (at the start of reperfusion). Given the lack of central nervous system effects and beneficial efficacy in the rat model of myocardial ischemia, it is felt that ARD-353 is the first nonpeptide delta-receptor agonist with true potential for clinical use before surgically induced ischemia or in an emergency setting.

Author List

Watson MJ, Holt JD, O'Neill SJ, Wei K, Pendergast W, Gross GJ, Gengo PJ, Chang KJ

MESH terms used to index this publication - Major topics in bold

Animals
Benzoates
Benzylidene Compounds
Binding, Competitive
Cardiotonic Agents
Catalepsy
Dose-Response Relationship, Drug
Hemodynamics
In Vitro Techniques
Male
Mice
Myocardial Infarction
Myocardial Reperfusion Injury
Myocardium
Naltrexone
Piperazines
Radioligand Assay
Rats
Rats, Sprague-Dawley
Receptors, Opioid, delta
Receptors, Opioid, kappa
Receptors, Opioid, mu
Reflex
Seizures