Literature DB >> 30924650

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

Sean P Henry1, Thomas J Fernandez, Jessica P Anand, Nicholas W Griggs, John R Traynor1, Henry I Mosberg1.   

Abstract

We have previously reported a series of μ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist ligands to serve as potential nonaddictive opioid analgesics. These ligands have been shown to be active in vivo, do not manifest withdrawal syndromes or reward behavior in conditioned-place preference assays in mice, and do not produce dependence. Although these attributes are promising, these analogues exhibit poor metabolic stability in mouse liver microsomes, likely due to the central tetrahydroquinoline scaffold in this series. As such, a structure-activity relationship (SAR) campaign was pursued to improve their metabolic stability. This resulted in a shift from our original bicyclic tetrahydroquinoline core to a monocyclic benzylic-core system. By eliminating one of the rings in this scaffold and exploring the SAR of this new core, two promising analogues were discovered. These analogues (5l and 5m) had potency and efficacy values at MOR better or comparable to morphine, retained their DOR-antagonist properties, and showed a 10-fold improvement in metabolic stability.

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Year:  2019        PMID： 30924650      PMCID： PMC6713576          DOI： 10.1021/acs.jmedchem.9b00219

Source DB:  PubMed          Journal:  J Med Chem        ISSN： 0022-2623            Impact factor:   7.446


  34 in total

1.  New series of potent delta-opioid antagonists containing the H-Dmt-Tic-NH-hexyl-NH-R motif.

Authors:  Tingyou Li; Kimitaka Shiotani; Anna Miyazaki; Yoshio Fujita; Yuko Tsuda; Akihiro Ambo; Yusuke Sasaki; Yunden Jinsmaa; Ewa Marczak; Sharon D Bryant; Lawrence H Lazarus; Yoshio Okada
Journal:  Bioorg Med Chem Lett       Date:  2005-09-23       Impact factor: 2.823

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.  In vivo pharmacological characterization of SoRI 9409, a nonpeptidic opioid mu-agonist/delta-antagonist that produces limited antinociceptive tolerance and attenuates morphine physical dependence.

Authors:  J L Wells; J L Bartlett; S Ananthan; E J Bilsky
Journal:  J Pharmacol Exp Ther       Date:  2001-05       Impact factor: 4.030

4.  Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice.

Authors:  Y Zhu; M A King; A G Schuller; J F Nitsche; M Reidl; R P Elde; E Unterwald; G W Pasternak; J E Pintar
Journal:  Neuron       Date:  1999-09       Impact factor: 17.173

5.  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

6.  Unique high-affinity synthetic mu-opioid receptor agonists with central- and systemic-mediated analgesia.

Authors:  Yoshio Okada; Yuko Tsuda; Yoshio Fujita; Toshio Yokoi; Yusuke Sasaki; Akihiro Ambo; Ryoji Konishi; Mitsuhiro Nagata; Severo Salvadori; Yunden Jinsmaa; Sharon D Bryant; Lawrence H Lazarus
Journal:  J Med Chem       Date:  2003-07-17       Impact factor: 7.446

7.  Preparation and opioid activity of analogues of the analgesic dipeptide 2,6-dimethyl-L-tyrosyl-N-(3-phenylpropyl)-D-alaninamide.

Authors:  N S Chandrakumar; P K Yonan; A Stapelfeld; M Savage; E Rorbacher; P C Contreras; D Hammond
Journal:  J Med Chem       Date:  1992-01-24       Impact factor: 7.446

8.  Novel 2',6'-dimethyl-L-tyrosine-containing pyrazinone opioid mimetic mu-agonists with potent antinociceptive activity in mice.

Authors:  Yunden Jinsmaa; Yoshio Okada; Yuko Tsuda; Kimitaka Shiotani; Yusuke Sasaki; Akihiro Ambo; Sharon D Bryant; Lawrence H Lazarus
Journal:  J Pharmacol Exp Ther       Date:  2004-01-12       Impact factor: 4.030

9.  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

10.  Oral bioavailability of a new class of micro-opioid receptor agonists containing 3,6-bis[Dmt-NH(CH(2))(n)]-2(1H)-pyrazinone with central-mediated analgesia.

Authors:  Yunden Jinsmaa; Anna Miyazaki; Yoshio Fujita; Tingyou Li; Yutaka Fujisawa; Kimitaka Shiotani; Yuko Tsuda; Toshio Yokoi; Akihiro Ambo; Yusuke Sasaki; Sharon D Bryant; Lawrence H Lazarus; Yoshio Okada
Journal:  J Med Chem       Date:  2004-05-06       Impact factor: 7.446
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  4 in total

1.  Aromatic-Amine Pendants Produce Highly Potent and Efficacious Mixed Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Peptidomimetics with Enhanced Metabolic Stability.

Authors:  Sean Henry; Jessica P Anand; Jack J Twarozynski; Ashley C Brinkel; Irina D Pogozheva; Bryan F Sears; Emily M Jutkiewicz; John R Traynor; Henry I Mosberg
Journal:  J Med Chem       Date:  2020-02-10       Impact factor: 7.446

2.  Structure-Activity Relationships of 7-Substituted Dimethyltyrosine-Tetrahydroisoquinoline Opioid Peptidomimetics.

Authors:  Deanna Montgomery; Jessica P Anand; Mason A Baber; Jack J Twarozynski; Joshua G Hartman; Lennon J Delong; John R Traynor; Henry I Mosberg
Journal:  Molecules       Date:  2019-11-26       Impact factor: 4.411

Review 3.  Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery.

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

4.  Targeting protein-protein interaction for immunomodulation: A sunflower trypsin inhibitor analog peptidomimetic suppresses RA progression in CIA model.

Authors:  Achyut Dahal; Pravin Parajuli; Sitanshu S Singh; Leeza Shrestha; Jafrin Jobayer Sonju; Prajesh Shrestha; Ioulia Chatzistamou; Seetharama Jois
Journal:  J Pharmacol Sci       Date:  2022-04-25       Impact factor: 3.578
  4 in total

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