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

Q3 · MEDICINE

Article

Author: 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.

01 Dec 2003·Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: 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.

The Delta Receptor

Author: Kwen-Jen Chang ; Frank Porreca ; James Haughton Woods

The Delta Receptor: History of Delta Opioid Receptors, Wen-Jen Chang Cloning of Delta Opioid Receptors, Arnaud Lacoste and Christopher J. Evans Cloning and Expression of the Human Delta Opioid Receptor, Richard J. Knapp, Ewa Malatynska, Eva V. Varga, William R. Roeske, and Henry I. Yamamura In Vitro and In Vivo Mutagenesis - Insights into Delta Receptor Structure and Function, F.M. Dicaillot and Brigiitte L. Kieffer Delta Opioid Receptor Signaling and Trafficking, P.Y. Law Delta Opioid Receptors and G Proteins, Mary J. Clark and John R. Traynor Transcriptional Regulation of Delta Opioid Receptor, Gene Ping Sun and Horace Loh. Delta Ligands: Benzhydrylpiperazines as Nonpeptidic Delta Opioid Receptor Ligands, Michael J. Bishop and Robert W. McNutt Delta-Selective Ligands Related to Naltrindole. D.J. Daniels and P.S. Portoghese Endogenous Peptides for Delta Opioid Receptors and Analogues, Victor J. Hruby and Henry I. Mosberg Deltorphins, Lucia Negri and Elisa Giannini Opioid Peptide--Derived Delta Antagonists, Inverse Agonists and Mixed Mu Agonists/Delta Antagonists. Peter W. Schiller Inverse Agonism at the Delta Opioid Receptors, Eva V. Varga, Keiko Hosohata, Yoshioko Hosohata, Jennifer Tsang, Thomas Burkey, Josue Alfaro-Lopez, Xuejun Tang, Victor R. Hruby, William R. Roeske and Henry I. Yamamura Mixed Opioid Receptor Agonists as a New Class of Agents for the Treatment of Moderate-to-Severe Pain, Peter J. Gengo and Kwen-Jen Chang Biphalin - A Multireceptor Opioid Ligand Binding and Activity of Opioid Ligands at the Cloned Human Delta, Mu and Kappa Receptors Andrez W. Lipkowski, Daniel B. Carr, Iwona Bonney and Aleksandra Misicka Kemal Payza Inhibitors of Enkephalin-Inactivating Enzymes and Delta Opioid Responses, Bernard P. Roques and Florence Noble. Pharmacology And Physiology: Delta Opioid Receptor Subtypes and Pain Modulation, Michael H. Ossipov, Josephine Lai, Todd W. Vanderah and Frank Porreca Delta Opioid Receptor-Mediated Antinociception/Analgesia Minoru Narita and Tsutomu Suzuki Antidepressant-like Effects of Delta Opioid Receptor Agonists, Emily M. Jutkiewicz and James H. Woods Mu-Delta Interactions In Vitro and In Vivo, Richard B. Rothman and Heng Xu Delta Opioids and Immune Function, Richard J. Weber and Ricardo Gomez-Flores Delta Opioids and Substance Abuse, S. Stevens Negus Delta Opioid Receptors in the Gastrointestinal Tract, DeWayne Townsend IV and David R. Brown Cardioprotection and Delta Opioid Receptors, Garrett J. Gross, Ryan M. Fryer, Hemal H. Patel and Joel J. Schultz The Delta Opioid Receptor and Brain Pain-Modulating Circuits, Mary M. Heinricher and Howard L. Fields.

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