Literature DB >> 24365161

Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands.

Aaron M Bender1, Mary J Clark2, Michael P Agius1, John R Traynor2, Henry I Mosberg3.   

Abstract

In this letter, we describe a series of 4-substituted piperidine and piperazine compounds based on tetrahydroquinoline 1, a compound that shows balanced, low nanomolar binding affinity for the mu opioid receptor (MOR) and the delta opioid receptor (DOR). We have shown that by changing the length and flexibility profile of the side chain in this position, binding affinity is improved at both receptors by a significant degree. Furthermore, several of the compounds described herein display good efficacy at MOR, while simultaneously displaying DOR antagonism. The MOR agonist/DOR antagonist has shown promise in the reduction of negative side effects displayed by selective MOR agonists, namely the development of dependence and tolerance.
Copyright © 2013 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  Mixed function opioids; Opioid peptidomimetics

Mesh：

Substances：

Year:  2013        PMID： 24365161      PMCID： PMC3919453          DOI： 10.1016/j.bmcl.2013.12.021

Source DB:  PubMed          Journal:  Bioorg Med Chem Lett        ISSN： 0960-894X            Impact factor:   2.823


  11 in total

1.  Development and in vitro characterization of a novel bifunctional μ-agonist/δ-antagonist opioid tetrapeptide.

Authors:  Lauren C Purington; Katarzyna Sobczyk-Kojiro; Irina D Pogozheva; John R Traynor; Henry I Mosberg
Journal:  ACS Chem Biol       Date:  2011-10-11       Impact factor: 5.100

2.  Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice.

Authors:  E E Abdelhamid; M Sultana; P S Portoghese; A E Takemori
Journal:  J Pharmacol Exp Ther       Date:  1991-07-01       Impact factor: 4.030

3.  Opioid peptidomimetics: leads for the design of bioavailable mixed efficacy μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands.

Authors:  Henry I Mosberg; Larisa Yeomans; Aubrie A Harland; Aaron M Bender; Katarzyna Sobczyk-Kojiro; Jessica P Anand; Mary J Clark; Emily M Jutkiewicz; John R Traynor
Journal:  J Med Chem       Date:  2013-02-27       Impact factor: 7.446

4.  Elucidation of the bioactive conformation of the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of mu-opioid receptor antagonists.

Authors:  Bertrand Le Bourdonnec; Allan J Goodman; Mathieu Michaut; Hai-Fen Ye; Thomas M Graczyk; Serge Belanger; Torsten Herbertz; Glenn P A Yap; Robert N DeHaven; Roland E Dolle
Journal:  J Med Chem       Date:  2006-12-14       Impact factor: 7.446

5.  New structural concepts for narcotic antagonists defined in a 4-phenylpiperidine series.

Authors:  D M Zimmerman; R Nickander; J S Horng; D T Wong
Journal:  Nature       Date:  1978-09-28       Impact factor: 49.962

6.  14-Alkoxy- and 14-acyloxypyridomorphinans: μ agonist/δ antagonist opioid analgesics with diminished tolerance and dependence side effects.

Authors:  Subramaniam Ananthan; Surendra K Saini; Christina M Dersch; Heng Xu; Nicholas McGlinchey; Denise Giuvelis; Edward J Bilsky; Richard B Rothman
Journal:  J Med Chem       Date:  2012-09-27       Impact factor: 7.446

7.  The opioid mu agonist/delta antagonist DIPP-NH(2)[Psi] produces a potent analgesic effect, no physical dependence, and less tolerance than morphine in rats.

Authors:  P W Schiller; M E Fundytus; L Merovitz; G Weltrowska; T M Nguyen; C Lemieux; N N Chung; T J Coderre
Journal:  J Med Chem       Date:  1999-09-09       Impact factor: 7.446

8.  Identification of a dual δ OR antagonist/μ OR agonist as a potential therapeutic for diarrhea-predominant Irritable Bowel Syndrome (IBS-d).

Authors:  Henry J Breslin; Craig J Diamond; Robert W Kavash; Chaozhong Cai; Alexey B Dyatkin; Tamara A Miskowski; Sui-Po Zhang; Paul R Wade; Pamela J Hornby; Wei He
Journal:  Bioorg Med Chem Lett       Date:  2012-05-24       Impact factor: 2.823

9.  Modulation of opioid receptor ligand affinity and efficacy using active and inactive state receptor models.

Authors:  Jessica P Anand; Lauren C Purington; Irina D Pogozheva; John R Traynor; Henry I Mosberg
Journal:  Chem Biol Drug Des       Date:  2012-09-12       Impact factor: 2.817

10.  Characterization of the complex morphinan derivative BU72 as a high efficacy, long-lasting mu-opioid receptor agonist.

Authors:  Claire L Neilan; Stephen M Husbands; Simon Breeden; M C Holden Ko; Mario D Aceto; John W Lewis; James H Woods; John R Traynor
Journal:  Eur J Pharmacol       Date:  2004-09-19       Impact factor: 4.432
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  8 in total

1.  Asymmetric synthesis and in vitro and in vivo activity of tetrahydroquinolines featuring a diverse set of polar substitutions at the 6 position as mixed-efficacy μ opioid receptor/δ opioid receptor ligands.

Authors:  Aaron M Bender; Nicholas W Griggs; Jessica P Anand; John R Traynor; Emily M Jutkiewicz; Henry I Mosberg
Journal:  ACS Chem Neurosci       Date:  2015-05-13       Impact factor: 4.418

2.  Structural Simplification of a Tetrahydroquinoline-Core Peptidomimetic μ-Opioid Receptor (MOR) Agonist/δ-Opioid Receptor (DOR) Antagonist Produces Improved Metabolic Stability.

Authors:  Sean P Henry; Thomas J Fernandez; Jessica P Anand; Nicholas W Griggs; John R Traynor; Henry I Mosberg
Journal:  J Med Chem       Date:  2019-04-12       Impact factor: 7.446

Review 3.  Molecular Pharmacology of δ-Opioid Receptors.

Authors:  Louis Gendron; Catherine M Cahill; Mark von Zastrow; Peter W Schiller; Graciela Pineyro
Journal:  Pharmacol Rev       Date:  2016-07       Impact factor: 25.468

4.  Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy μ-Opioid Receptor (MOR) Agonists/δ-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities.

Authors:  Aubrie A Harland; Larisa Yeomans; Nicholas W Griggs; Jessica P Anand; Irina D Pogozheva; Emily M Jutkiewicz; John R Traynor; Henry I Mosberg
Journal:  J Med Chem       Date:  2015-11-13       Impact factor: 7.446

5.  Rapid Synthesis of Boc-2',6'-dimethyl-l-tyrosine and Derivatives and Incorporation into Opioid Peptidomimetics.

Authors:  Aaron M Bender; Nicholas W Griggs; Chao Gao; Tyler J Trask; John R Traynor; Henry I Mosberg
Journal:  ACS Med Chem Lett       Date:  2015-10-19       Impact factor: 4.345

6.  Crystal structures of 4-phenyl-piperazin-1-ium 6-chloro-5-ethyl-2,4-dioxopyrimidin-1-ide and 4-phenyl-piperazin-1-ium 6-chloro-5-isopropyl-2,4-dioxopyrimidin-1-ide.

Authors:  Monirah A Al-Alshaikh; Ali A El-Emam; Omar A Al-Deeb; Mohammed S M Abdelbaky; Santiago Garcia-Granda
Journal:  Acta Crystallogr E Crystallogr Commun       Date:  2015-07-22

Review 7.  Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery.

Authors:  Yeon Sun Lee
Journal:  Biomolecules       Date:  2022-09-05

8.  The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of "Tail Wags Dog" Experiments.

Authors:  Meining Wang; Thomas C Irvin; Christine A Herdman; Ramsey D Hanna; Sergio A Hassan; Yong-Sok Lee; Sophia Kaska; Rachel Saylor Crowley; Thomas E Prisinzano; Sarah L Withey; Carol A Paronis; Jack Bergman; Saadet Inan; Ellen B Geller; Martin W Adler; Theresa A Kopajtic; Jonathan L Katz; Aaron M Chadderdon; John R Traynor; Arthur E Jacobson; Kenner C Rice
Journal:  Molecules       Date:  2020-06-06       Impact factor: 4.411
  8 in total

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