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.
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.
Watson
Michael J
MJ
Enhance Biotech Inc., 631 United Drive, Suite 200, Durham, NC 27713, USA.
Holt
Jonathon D S
JD
O'Neill
Scott J
SJ
Wei
Ke
K
Pendergast
William
W
Gross
Garrett J
GJ
Gengo
Peter J
PJ
Chang
Kwen-Jen
KJ
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002316:Cardiotonic Agents; D002375:Catalepsy / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology; D009206:Myocardium / Q000473:pathology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017473:Receptors, Opioid, kappa / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects; D012018:Reflex / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control
C509076:4-(4-((4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-1-ylmethyl)benzoic acid; D001565:Benzoates; D001597:Benzylidene Compounds; D002316:Cardiotonic Agents; D010879:Piperazines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C077358:7-benzylidenenaltrexone; D009271:Naltrexone