Abstract
A novel δ-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 δ receptor selectivity using radioligand binding and had no apparent selectivity between δ receptor subtypes as determined by [3H] cyclic [d-Pen2,d-Pen5]enkephalin (δ1) and [3H]Deltorphin II (δ2) competition binding. ARD-353 also showed selective δ 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 δ1-opioid selective antagonist 7-benzylidenenaltrexone, indicating a significant role for the δ1-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 δ-receptor agonist with true potential for clinical use before surgically induced ischemia or in an emergency setting.
Footnotes
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Some of these data were presented at Experimental Biology, 2005 [Watson MJ, Holt JDS, O'Neill SJ, Wei K, Pendergast W, Gengo PJ, Gross GJ, and Chang K-J (2005) Acute and chronic cardioprotective effects of a novel, δ-opioid receptor agonist ARD-353 in rats (Abstract). FASEB J19:A1562] and the International Society for Heart Research, 2005 [Holt JDS, Watson MJ, and Chang K-J (2005) ARD-353: a cardioprotective δ receptor agonist active before ischemia and immediately post-ischemic insult (Abstract). J Mol Cell Cardiol38:834].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.092742.
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ABBREVIATIONS: IPC, ischemic preconditioning; ARD-353, 4-((2R,5S)-4-(R)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-1-ylmethyl)benzoic acid; CNS, central nervous system; DPDPE, cyclic [d-Pen2,d-Pen5] enkephalin; DAMGO, [d-Ala,N-Me-Phe,Gly-ol]-enkephalin; U69593, (+)-(5α,7α,8β)-N-methyl-N-(7-(1-pyrrolidinyl)-1 oxaspiro[4.5] dec-8-yl)benzeneacetamide; TIPP, Tyr-Tic-Phe-Phe; CTOP, cyclic [d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2]; BW373U86, (±)-[1(S*),2α,5β]-4-{[2,5-dimethyl-4-(2-propenyl)-1-piperazinyl](3-hydroxypheny)methyl}-N,N-diethylbenzamide; LAD, left anterior descending coronary artery; BNTX, 7-benzylidenenaltrexone; DMSO, dimethyl sulfoxide; AAR, area at risk; IS, infarct size; TAN-67, 2-methyl-4a α-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a α-octahydro-quinolino[2,3,3-g]isoquinoline.
- Received July 26, 2005.
- Accepted September 26, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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