作者: Wang, Li-Li ; Li, Yu-Lei ; Cui, Ben-Qiang ; Zhou, Pei-Lan ; Yu, Gang ; Su, Rui-Bin ; Wang, Ying-Fei ; Pan, Chen-Ling ; Yi, Shou-Pu ; Kong, Qing-Hong ; Chang, Kwen-Jen ; Gong, Ze-Hui ; Wang, Guan-Lin ; Yu, Jie ; Shen, Yue-Hai

Opioid analgesics remain the first choice for the treatment of moderate to severe pain, but they are also notorious for their respiratory depression and addictive effects. This study focused on the pharmacology of a novel opioid receptor mixed agonist DPI-125 and attempted to elucidate the relationship between the δ-, μ- and κ-receptor potency ratio and respiratory depression and abuse liability. Five diarylmethylpiperazine compounds (DPI-125, DPI-3290, DPI-130, KUST202 and KUST13T02) were selected for this study. PKA fluorescence redistribution assays in CHO cells individually expressing δ-, μ- or κ-receptors were used to measure the agonist potency. The respiratory safety profiles were estimated in rats by the ratio of ED₅₀ (pCO₂ increase)/ED₅₀ (antinociception). The abuse liability of DPI-125 was evaluated with a self-administration model in rhesus monkeys. The observed agonist potencies of DPI-125 for δ-, μ- and κ-opioid receptors were 4.29±0.36, 11.10±3.04, and 16.57±4.14 nmol/L, respectively. The other four compounds were also mixed agonists with varying potencies. DPI-125 exhibited a high respiratory safety profile, clearly related to its high δ-receptor potency. The ratio of the EC₅₀ potencies for the μ- and δ-receptors was found to be positively correlated with the respiratory safety ratio. DPI-125 has similar potencies for μ- and κ-receptors, which is likely the reason for its reduced abuse potential. Our results demonstrate that the opioid receptor mixed agonist DPI-125 is safer and less addictive than traditional μ-agonist analgesics. These findings suggest that the development of δ>μ∼κ opioid receptor mixed agonists is feasible, and such compounds could represent a promising class of potent analgesics with wider therapeutic windows.

2003-12-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

DPI-3290 [(+)-3-((α-R)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. II. A Mixed Opioid Agonist with Potent Antinociceptive Activity and Limited Effects on Respiratory Function

3区 · 医学

Article

作者: O'Neill, Scott J. ; McNutt, Robert ; Su, Ying Fu ; Pettit, Hugh O. ; Chang, Kwen-jen ; Gengo, Peter J.

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, (+)-3-((alpha-R)-alpha-((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 +/- 0.0072 mg/kg. Simultaneous measurement of arterial blood gas in animals treated with DPI-3290 demonstrated dose-dependent increases in pCO2 with an ED(50) value of 0.91 +/- 0.22 mg/kg. In comparison, morphine and fentanyl increased antinociception in rats with ED(50) values of 2.01 +/- 0.0005 and 0.0034 +/- 0.00024 mg/kg, respectively, and the ED(50) value for morphine-induced changes in pCO2 was 4.23 +/- 0.72 mg/kg, whereas the ED(50) value for fentanyl-induced changes in pCO2 was 0.0127 +/- 0.0035 mg/kg. A separate series of experiments were designed to examine the effects of DPI-3290 on mu-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 microg/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 pCO2; 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 mu-opioid receptor-mediated hypercapnia.

2003-12-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

DPI-3290 [(+)-3-((α-R)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. I. A Mixed Opioid Agonist with Potent Antinociceptive Activity

3区 · 医学

Article

作者: Wei, Ke ; O'Neill, Scott J. ; Bishop, Michael J. ; McNutt, Robert ; Pettit, Hugh O. ; Chang, Kwen-jen ; Gengo, Peter J.

Compound (+)-3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide (DPI-3290), 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 degrees C using membranes from rat brain or guinea pig cerebellum, the Ki values measured for DPI-3290 at delta-, mu-, and kappa-opioid receptors were 0.18 +/- 0.02, 0.46 +/- 0.05, and 0.62 +/- 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 IC50 values of 1.0 +/- 0.3, 6.2 +/- 2.0, and 25.0 +/- 3.3 nM at delta-, mu-, and kappa-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 delta-, mu-, and kappa-receptors, respectively. In ileal strips isolated from guinea pigs, DPI-3290 inhibited tension development with a corresponding IC50 value of 3.4 +/- 1.6 nM at mu-opioid receptors and 6.7 +/- 1.6 nM at kappa-opioid receptors. Intravenous administration of 0.05 +/- 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.

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