4‘-Arylpyrrolomorphinans:  Effect of a Pyrrolo-<i>N</i>-benzyl Substituent in Enhancing δ-Opioid Antagonist Activity

Srivastava, Sanjay K.; Husbands, Stephen M.; Aceto, Mario D.; Miller, Claudia; Traynor, John R.; Lewis, John W.

doi:10.1021/jm010841w

Cited by 15 publications

(22 citation statements)

References 20 publications

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“…Among a limited number of such pyrrolomorphinans synthesized and evaluated, it was found that compound 16 possessing a 4-methylphenyl substituent on the pyrrole ring displayed ␦ antagonist activity with a K e of 14.1 nM and partial agonist activity with and EC 50 of 1360 nM and E max of 34% in [ 35 S]GTP ␥ S binding assays in CHO cells expressing human ␦ and opioid receptors. 63 Portoghese and coworkers have, for a long time, pursued the design of bivalent ligands to probe opioid receptor complexes. [64][65][66][67] The recent demonstration of the existence of -␦ receptor hetero-oligomeric complexes has spurred further interest in the design of such bivalent ligands that could potentially interact with these receptor complexes.…”

Section: E122mentioning

confidence: 99%

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

Ananthan

2006

AAPS J

126

110

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A BSTRACTOpioids are widely used in the treatment of severe pain. The clinical use of the opioids is limited by serious side effects such as respiratory depression, constipation, development of tolerance, and physical dependence and addiction liabilities. Most of the currently available opioid analgesics exert their analgesic and adverse effects primarily through the opioid receptors. A large number of biochemical and pharmacological studies and studies using genetically modifi ed animals have provided convincing evidence regarding the existence of modulatory interactions between opioid and ␦ receptors. Several studies indicate that ␦ receptor agonists as well as ␦ receptor antagonists can provide benefi cial modulation to the pharmacological effects of agonists. For example, ␦ agonists can enhance the analgesic potency and effi cacy of agonists, and ␦ antagonists can prevent or diminish the development of tolerance and physical dependence by agonists. On the basis of these observations, the development of new opioid ligands possessing mixed agonist/ ␦ agonist profi le and mixed agonist/ ␦ antagonist profi le has emerged as a promising new approach to analgesic drug development. A brief overview of -␦ interactions and recent developments in identifi cation of ligands possessing mixed agonist/ ␦ agonist and agonist/ ␦ antagonist activities is provided in this report. K EYWORDS:Analgesics , Opioid Ligands , Mixed Mu/Delta agonists , Mixed Mu agonist/Delta antagonists , Peptides , Nonpeptides INTRODUCTIONOpioid analgesics are the standard therapeutic agents for the treatment of moderate-to-severe pain. These drugs exert their analgesic activity through their interaction with the opioid , ␦ , or receptors as agonists. The clinical usefulness of opioid agonists such as morphine, however, is limited by signifi cant side effects such as respiratory depression, constipation, development of tolerance and physical dependence, and addiction potential. One approach to limit -receptor-mediated side effects is to selectively target ␦ and opioid receptors. This approach has been explored using agonist ligands selective for ␦ and opioid receptors but has seen only limited success. The ␦ agonists generally display limited analgesic effi cacy and receptor agonists are limited to their use as peripheral analgesics owing to their psychotomimetic and dysphoric central effects. An alternative approach that is gaining considerable interest is the development of compounds that possess mixed opioid activity at the different opioid receptors. 1 , 2 Several lines of evidence indicate the existence of physical and functional interactions between the opioid receptors, particularly between the and ␦ receptors. Several biochemical and pharmacological studies using and ␦ receptor ligands gave an early indication of such interactions between the and ␦ receptors. [3][4][5][6] The and ␦ opioid receptors exist on overlapping populations of neurons in painmodulating regions of the central nervous system, and the presence of both and ␦ receptors ...

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Section: E122mentioning

confidence: 99%

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

Ananthan

2006

AAPS J

126

110

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“…DOPr antagonist potency and selectivity was restored in 6a by pyrrole-ring substitution in the 4′ and 5′-positions as in 6b , 13 with further enhancement of DOPr potency by introduction of a 1′(N)-benzyl substituent as in 3a . 5 The herein reported example ( 4b ) is a non-selective opioid antagonist which is best compared with 6b since a side chain CO 2 Et is regarded as an isostere of a phenyl group 14 so that the 4′-benzyl group of 6b is comparable to the 4′-CH 2 CO 2 Et group of 4b . Despite the structural differences between 6b and 4b in the 1′-(N) and 5′-positions (substituents R 1 and R 3 in structure 6 ) they have comparable DOPr antagonist potency (Ke 6b 2.1nM, 4b 6.8nM) but equally high MOPr (6.6 nM) and KOPr (4.3 nM) antagonist potencies of 4b means DOPr antagonist selectivity in 4b is lost whereas 6b was 50-fold selective over both MOPr and KOPr.…”

Section: Discussionmentioning

confidence: 89%

“…Despite the structural differences between 6b and 4b in the 1′-(N) and 5′-positions (substituents R 1 and R 3 in structure 6 ) they have comparable DOPr antagonist potency (Ke 6b 2.1nM, 4b 6.8nM) but equally high MOPr (6.6 nM) and KOPr (4.3 nM) antagonist potencies of 4b means DOPr antagonist selectivity in 4b is lost whereas 6b was 50-fold selective over both MOPr and KOPr. 13 Since it was established that the 1′-(N)-benzyl group had a positive effect particularly on DOPr antagonist potency, 5 it appears that the 5′-hydroxyl group has the opposite effect.…”

Section: Discussionmentioning

confidence: 99%

“…The reactions of γ-nitrostyrenes with the imines generated in-situ produced 4′-aryl-1-benzylpyrrolomorphinan ligands ( 3 ). 5 These ligands had modest selectivity in receptor binding assays for DOPr over KOPr but not over MOPr. In the [ 35 S]GTPγS assays they showed predominantly opioid receptor antagonist activity with substantial DOPr selectivity particularly over KOPr.…”

Section: Introductionmentioning

confidence: 98%

“…The lead compound ( 3a ) in vivo had slow onset as an antagonist of the selective DOPr agonist SNC80 with potency comparable to that of NTI. 5 …”

Section: Introductionmentioning

confidence: 99%

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Pyrrolo- and pyridomorphinans: Non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists

Kumar

Clark

Traynor

et al. 2014

Bioorganic & Medicinal Chemistry

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Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse.

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Michael Reactions of Benzylimines Derived from Morphinan-6-ones: Synthesis of Pyrrolo- and Pyridinomorphinans

Shefali¹,

Srivastava²,

Hall³

et al. 2002

HCA

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The benzylimines 15 derived from oxymorphones 14 and generated in situ reacted with Michael acceptors (methyl methacrylate, maleic anhydride, and a-methylene-g-butyrolactone) to give opioid ligands 16, 17, and 19 ± 21 having pyrrole-or pyridine-derived ring systems (see Scheme 3). The product of the reaction with maleic anhydride displayed a surprising preference for the 2-hydroxypyrrole form 19 rather than for the tautomeric 1,6dihydro-2H-pyrrol-2-one form 24, resulting from the stability of the C(6)C(7) bond in oxymorphone and related structures.Scheme 2 i) Maleic anhydride, 0 ± 208, 10 min. ii) Methyl methacrylate, 1008, 3d. iii) Methyl crotonate, 1208, 5d.

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4‘-Arylpyrrolomorphinans: Effect of a Pyrrolo-N-benzyl Substituent in Enhancing δ-Opioid Antagonist Activity

Cited by 15 publications

References 20 publications

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

Pyrrolo- and pyridomorphinans: Non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists

Michael Reactions of Benzylimines Derived from Morphinan-6-ones: Synthesis of Pyrrolo- and Pyridinomorphinans

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