Methylation Products of 6β- N-Heterocyclic Substituted Naltrexamine Derivatives as Potential Peripheral Opioid Receptor Modulators

ACS Chemical Neuroscience
Yi ZhengYan Zhang

Abstract

Two 6β- N-heterocyclic naltrexamine derivatives, NAP and NMP, have been identified as peripherally selective mu opioid receptor (MOR) antagonists. To further enhance the peripheral selectivity of both compounds, the 17-amino group and the nitrogen atom of the pyridine ring in both NAP and NMP were methylated to obtain dMNAP and dMNMP, respectively. Compared with NAP and NMP, the binding affinities of dMNAP and dMNMP shifted to MOR and KOR (kappa opioid receptor) dual selective and they acted as moderate efficacy partial agonists. The results from radioligand binding studies were further confirmed by molecular docking studies. In vivo studies demonstrated that dMNAP and dMNMP did not produce antinociception nor did they antagonize morphine's antinociceptive activity, indicating that these compounds did not act on the central nervous system. Meanwhile, both dMNAP and dMNMP significantly slowed down fecal excretion, which indicated that they were peripherally acting opioid receptor agonists. All together, these results suggested that dMNAP and dMNMP acted as peripheral mu/kappa opioid receptor modulators and may be applicable in the treatment of diarrhea in patients with bowel dysfunction.

References

Jun 1, 1988·Gastroenterology·P N KaufmanR S Fisher
Aug 1, 1995·Drug and Alcohol Dependence·L J CheskinJ H Jaffe
Jan 1, 1996·Pharmacology & Therapeutics·A De Luca, I M Coupar
Apr 4, 1997·Journal of Molecular Biology·G JonesR Taylor
Dec 22, 1999·Pain·W MeissnerK Reinhart
Apr 20, 2001·Current Pain and Headache Reports·D M Thorpe
Jan 5, 2002·American Journal of Surgery·M Pappagallo
Nov 19, 2003·The Journal of Pain : Official Journal of the American Pain Society·Ewan McNicolUNKNOWN Americal Pain Society
Mar 31, 2004·British Journal of Pharmacology·Pierre J-M Rivière
Sep 11, 2004·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·J D Wood, J J Galligan
Jun 21, 2005·Journal of Pharmacological and Toxicological Methods·S W MittelstadtR D Spruell
Mar 28, 2008·Alimentary Pharmacology & Therapeutics·S F CookS E Fehnel
May 30, 2008·The New England Journal of Medicine·Jay ThomasRobert J Israel
Aug 7, 2008·The Journal of Pharmacology and Experimental Therapeutics·Gracious R RossHamid I Akbarali
Aug 30, 2008·Pain Medicine : the Official Journal of the American Academy of Pain Medicine·Timothy J BellRussell Williamson
Aug 5, 2009·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·J FichnaM A Storr
Aug 12, 2009·Journal of Pain & Palliative Care Pharmacotherapy·Sean D CandrilliShrividya Iyer
Jan 7, 2011·The New England Journal of Medicine·Mark PimentelUNKNOWN TARGET Study Group
Jun 21, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Pallabi MitraPhillip M Gerk
Dec 2, 2011·The Journal of Pharmacology and Experimental Therapeutics·Minho KangHamid I Akbarali
Mar 23, 2012·Nature·Aashish ManglikSébastien Granier
Mar 23, 2012·Nature·Huixian WuRaymond C Stevens
May 19, 2012·Nature·Sébastien GranierBrian K Kobilka
Dec 14, 2012·Nature·Jérémy BesnardAndrew L Hopkins
Apr 16, 2013·Gastroenterology·Leonard S DovePaul S Covington
Apr 30, 2013·Neuropharmacology·Gavril W Pasternak
Sep 21, 2013·Journal of Psychopharmacology·David J Nutt
Sep 27, 2014·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·H I AkbaraliW L Dewey
May 20, 2015·European Journal of Pharmacology·Yi Shang, Marta Filizola
Aug 8, 2015·Nature·Weijiao HuangBrian K Kobilka
Sep 4, 2015·Annual Review of Medicine·Christoph Stein

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