The opioid receptor triple agonist DPI-125 produces analgesia with less respiratory depression and reduced abuse liability

Acta Pharmacologica Sinica
Shou-Pu YiKwen-Jen Chang

Abstract

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...Continue Reading

References

Oct 1, 1989·Drug and Alcohol Dependence·G WingerJ H Woods
Jan 27, 1988·European Journal of Pharmacology·P S PortogheseA E Takemori
Aug 15, 1986·Science·A PfeifferH M Emrich
Sep 1, 1966·Japanese Journal of Pharmacology·H TakagiM Nakama
May 19, 1998·Trends in Pharmacological Sciences·Z Z Pan
Jan 6, 2000·Nature Cell Biology·M ZaccoloT Pozzan
Jun 8, 2000·The Journal of Biological Chemistry·S R GeorgeB F O'Dowd
May 1, 2001·Journal of Molecular Biology·A FelicielloE V Avvedimento
Mar 15, 2003·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Carrie A BowenNancy K Mello
Sep 1, 1954·British Journal of Pharmacology and Chemotherapy·C BIANCHI, J FRANCESCHINI
Mar 27, 2004·Proceedings of the National Academy of Sciences of the United States of America·Ivone GomesLakshmi A Devi
Jul 1, 2006·Molecular Interventions·Emily M Jutkiewicz
May 6, 2008·British Journal of Anaesthesia·K T S Pattinson
Oct 8, 2008·Experimental and Clinical Psychopharmacology·S Stevens NegusGlenn W Stevenson
Aug 24, 2010·Acta Pharmacologica Sinica·Yu-hua WangJing-gen Liu
Mar 19, 2011·Molecular Pharmacology·Ivone GomesLakshmi A Devi
Dec 30, 2011·Current Drug Targets·Yuan FengYing Xia
Mar 23, 2012·Nature·Aashish ManglikSébastien Granier
Mar 23, 2012·Nature·Huixian WuRaymond C Stevens
May 12, 2012·Nature·Alastair M Thompson
May 19, 2012·Nature·Sébastien GranierBrian K Kobilka
Aug 4, 2012·ACS Chemical Neuroscience·Matthew D MetcalfPhilip S Portoghese
Sep 28, 2012·Cellular and Molecular Life Sciences : CMLS·Xiaozhou HeYing Xia
Jan 15, 2014·Nature·Gustavo FenaltiRaymond C Stevens
May 27, 2014·Pharmacology, Biochemistry, and Behavior·T J HudzikM D B Swedberg
Aug 8, 2015·Nature·Rémy SounierSébastien Granier
Aug 8, 2015·Nature·Weijiao HuangBrian K Kobilka

❮ Previous
Next ❯

Related Concepts

Related Feeds

Addiction

This feed focuses mechanisms underlying addiction and addictive behaviour including heroin and opium dependence, alcohol intoxication, gambling, and tobacco addiction.