A novel ␦-receptor selective compound, 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 ␦ receptor selectivity using radioligand binding and had no apparent selectivity between ␦ receptor subtypes as determined by 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 vehicletreated controls. The effects of ARD-353 on infarct size were blocked by the ␦ 1 -opioid selective antagonist 7-benzylidenenaltrexone, indicating a significant role for the ␦ 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 ␦-receptor agonist with true potential for clinical use before surgically induced ischemia or in an emergency setting.Ischemic preconditioning (IPC) is a physiological method of reducing injury to the myocardium after short-term ischemia and reperfusion that has demonstrated some potential for clinical efficacy (Murry et al., 1986). Repeated cycling of short episodes of ischemia induces changes in the myocardial cell signaling systems that seem to condition the myocytes to be resistant to ischemic and reperfusion damage. The ATPsensitive potassium channel (Gross and Auchampach, 1992), G i proteins (Lasley and Mentzer, 1993;Thornton et al., 1993), protein kinase C (Ytrehus et al., 1994), and the Na ϩ /H ϩ exchanger (Rohmann et al., 1995;Bugge et al., 1996;Piper et al., 1996) have all been implicated as part of the cellular mechanism of ischemic preconditioning. In addition to these messenger systems, several receptors have been Article, publication date, and citation information can be found at

Compound (ϩ)-3-((␣-R)-␣-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide , is one of a series of novel centrally acting agents with potent antinociceptive activity that binds specifically and with high affinity to opioid receptors. In saturation equilibrium binding studies performed at 25°C using membranes from rat brain or guinea pig cerebellum, the K i values measured for DPI-3290 at ␦-, -, and -opioid receptors were 0.18 Ϯ 0.02, 0.46 Ϯ 0.05, and 0.62 Ϯ 0.09 nM, respectively. In vas deferens isolated from laboratory mice, DPI-3290 decreased electrically induced tension development in a concentration-dependent manner with corresponding IC 50 values of 1.0 Ϯ 0.3, 6.2 Ϯ 2.0, and 25.0 Ϯ 3.3 nM at ␦-, -, and -receptors, respectively. The activity of DPI-3290 in isolated vas deferens tissue was approximately 20,000, 175.8, and 1500 times more efficacious than morphine, and 492, 2.5, and 35 times more efficacious than fentanyl at ␦-, -, and -receptors, respectively. In ileal strips isolated from guinea pigs, DPI-3290 inhibited tension development with a corresponding IC 50 value of 3.4 Ϯ 1.6 nM at -opioid receptors and 6.7 Ϯ 1.6 nM at -opioid receptors. Intravenous administration of 0.05 Ϯ 0.007 mg/kg DPI-3290 produced a 50% antinociceptive response in rats. The antinociceptive properties of DPI-3290 were blocked by naloxone (0.5 mg/kg s.c.). Compared with morphine, this study demonstrated that DPI-3290 is more potent and elicited a similar magnitude of antinociceptive activity in the rat, actions mediated by its mixed opioid receptor agonist activity. The marked antinociceptive activity of DPI-3290 will likely provide a means for relieving severe pain in patients that require analgesic treatment.Nucleotide sequences for three distinct pertussis toxinsensitive heterotrimeric GTP binding protein-coupled opioid receptors have been reported with approximately 65% homology existing between their amino acids (Kieffer et al., 1992; Chen et al., 1993a,b). These distinct opioid receptors termed , ␦, and are the binding sites for the endogenous peptide molecules endorphins, enkephalins, and dynorphins that have been shown to elicit a variety of pharmacological actions (Chang, 1984). The most notable of these opioid receptormediated actions is analgesia.Opioids produce their therapeutic effects by acting at the same receptors as the endogenous opioid peptides (Erspamer et al., 1989). They alter synaptic transmission by modulating the presynaptic release of neurotransmitters such as acetylcholine, norepinephrine, serotonin, dopamine, and substance P (Hagelberg et al., 2002). Changes in receptor-operated potassium currents, adenylate cyclase activity and intracellular free ionized calcium concentrations all have been reported to contribute to these changes in synaptic transmission (Fan and Crain, 1995;Murthy and Makhlouf, 1996). To date, hyperpolarization of membrane potential and the corresponding effects on voltage-sensitive calcium channels (Tang et al., 1994) togeth...

There is a wealth of information from animal models and clinical opioid-analgesic use that indicates a significant role for opioid receptors in the modulation of bladder activity. The novel benzhydrylpiperazine compound DPI-221 [4-((␣-S)-␣-((2S,5R)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide] was characterized as having ␦ receptor selectivity using radioligand binding (K i ϭ 2.0 Ϯ 0.7 nM, ␦ receptor; 1800 Ϯ 360 nM, receptor; and 2300 Ϯ 680 nM, receptor), and agonist activity was demonstrated in the mouse isolated vas deferens where DPI-221 inhibited electrically induced contractions with an IC 50 value of 88 Ϯ 7.5 nM. In the guinea pig isolated ileum, DPI-221 had no effect on electrically induced contractions at concentrations as high as 1 M. Sterile saline was infused (7 ml/h) into the bladder of Sprague-Dawley rats, via a transmural catheter; DPI-221 (1.0 to 20 mg/kg p.o.) significantly increased the interval between micturition events, whereas peak void pressure was not significantly decreased by any dose of DPI-221. The micturition effects of 10 mg/kg p.o. DPI-221 were blocked by naltrindole, indicating a ␦ receptor mechanism of action. In isolated rat bladder strips, DPI-221 was ineffective at relaxing detrusor muscle precontracted with carbachol. The most crucial safety aspect of ␦ agonist administration is the incidence of seizure-like convulsions in rodents. DPI-221 produced no convulsions at doses up to 100 mg/kg p.o. in mice, although rapid bolus i.v. injection of 5 mg/kg produced convulsions in 3% of mice tested. These findings indicate a good safety profile for DPI-221 administered orally, with potent efficacy in modifying bladder activity.Overactive bladder (OAB) and the associated urinary incontinence are widely prevalent; yet, the exact etiology of overactive bladder has not been fully elucidated. The basic principle of incontinence is an imbalance in the control of detrusor muscle tension in the bladder wall and the maintenance of a tightly closed urethral sphincter (Hudman et al., 2000). The regulation of these systems occurs through afferent A␦-fibers and (in the case of spinal disruption) C-fibers, whereas efferent fibers facilitate reflex and voluntary control at spinal, supraspinal, and central levels involving the pontine micturition center and the periaquaductal gray matter (Fowler, 2002). However, since the immediate innervation of the bladder is through acetylcholinergic neuromuscular junctions, most pharmacotherapies are based, at least partly, around the muscarinic cholinergic system. Unfortunately, current pharmacological treatments for OAB and urinary incontinence have incomplete efficacy while causing diverse side effects through muscarinic receptor effects or nonspecific cardiovascular effects (Ouslander, 2004).The ability of morphine and other opioids to inhibit reflex activity of the urinary bladder was demonstrated by several groups in the early 1980s (Brent et al., 1983; Dray and Metsch, 1984a,b,c;Hisamitsu and de Groat, 1984;Jubelin et a...

Allyl-2,5-dimethyl-1-piperazines have been of interest as analgesic agents for the management of moderate-to-severe pain. In this study, we compared the antinociceptive properties and respiratory depressant activity of one such agent, (ϩ)-3-((␣-R)-␣-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide (DPI-3290), with those of established narcotic analgesics, morphine and fentanyl. Intravenous administration of DPI-3290 in conscious laboratory rats increased antinociception in a dose-dependent manner with a corresponding ED 50 value of 0.05 Ϯ 0.0072 mg/kg. Simultaneous measurement of arterial blood gas in animals treated with DPI-3290 demonstrated dose-dependent increases in pCO 2 with an ED 50 value of 0.91 Ϯ 0.22 mg/kg. In comparison, morphine and fentanyl increased antinociception in rats with ED 50 values of 2.01 Ϯ 0.0005 and 0.0034 Ϯ 0.00024 mg/kg, respectively, and the ED 50 value for morphine-induced changes in pCO 2 was 4.23 Ϯ 0.72 mg/kg, whereas the ED 50 value for fentanyl-induced changes in pCO 2 was 0.0127 Ϯ 0.0035 mg/kg. A separate series of experiments were designed to examine the effects of DPI-3290 on -opioid receptor induced antinociception and hypercapnia. Intravenous bolus doses of DPI-3290 that ranged from 0.2 to 1.0 mg/kg had no effect on antinociception mediated by alfentanil (2 g/kg/min i.v.) but reduced hypercapnia by approximately 50%. Results from these studies demonstrate the equivalent antinociceptive efficacy of DPI-3290, morphine, and fentanyl but dramatic differences in the hypercapnia that antinociceptive doses of these drugs produce. When measured simultaneously, DPI-3290 had an 18.2-fold difference in the ratio comparing the ED 50 value for antinociception with the ED 50 value for changes in pCO 2 ; this ratio was 2.1 for morphine and 3.7 for fentanyl. Furthermore, DPI-3290 reduced the alfentanil-mediated hypercapnia without any effect on antinociception. Together, the balanced opioid agonist activity of DPI-3290 may provide a means of powerful analgesia while mitigating the -opioid receptor-mediated hypercapnia.Pain management is a major therapeutic challenge for which opioid analgesics are the mainstay in the treatment of moderate-to-severe pain (Inturrisi, 1990;Clotz and Nahata, 1991;Holder et al., 1995;Mason, 1999). These agents, which have powerful analgesic action, have been used for 200 years in spite of their narrow therapeutic index and their participation in deleterious drug-drug interactions. Adverse effects commonly associated with the use of narcotic analgesics include respiratory depression, nausea and vomiting, constipation, bradycardia, hypotension, hallucinations, euphoria, tolerance, dependence, and addiction potential (Chang, 1984;Inturrisi, 1990;Reisine and Pasternak, 1993). The most lifethreatening of these adverse effects is respiratory depression, which accounts for a majority of the resulting deaths, linked to the use of narcotic analgesics (Inturrisi, 1990;Reisine and Pasternak, 1993).Despite numerous...

Opioid analgesics with both micro and delta opioid receptor activation represent a new approach to the treatment of severe pain with an improved safety profile. Compounds with this profile may exhibit strong analgesic properties due to micro agonism, with a reduced side effect profile resulting from delta agonism. Replacing the p-diethylamide of the known potent delta opioid receptor selective agonist BW373U86 with a m-diethylamide resulted in a compound with agonist activity at both the micro and delta opioid receptors. Modifying the amide to an N-methyl-N-phenylamide increased agonist potency at both receptors. A series of 3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides have been made to explore the structure-activity relationship (SAR) around the N-methyl-N-phenylamide. Several potent agonists of both the micro and delta opioid receptors have been identified, including (+)-3-((alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylbenzamide (23), which has EC50 values of 0.67 and 1.1 nM at the micro (guinea pig ileum assay) and delta (mouse vas deferens assay) opioid receptors, respectively.