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.