Recent advances in selective opioid receptor agonists and antagonists

Eguchi, Masakatsu

doi:10.1002/med.10059

Cited by 145 publications

(117 citation statements)

References 171 publications

(147 reference statements)

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“…Naloxone and naltrexone, although pure mu antagonists, are only moderately selective for the mu opioid receptor. [12] In 1981, Portoghese described the first selective mu opioid antagonist, b-funaltrexamine (b-FNA) 11 (Figure 3), a site-directed alkylating agent that binds covalently to mu opioid receptors. [13] b-FNA, an analogue of b-naltrexamine 10, initially binds to all three opioid receptors, but because of very subtle structural differences within the receptor subtypes this compound alkylates, in vitro, only mu opioid receptors.…”

Section: Morphinansmentioning

confidence: 99%

Mu Opioid Receptor Antagonists: Recent Developments

2007

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For thousands of years mu opioid agonists such as morphine have been utilized for their analgesic properties. Today, morphine and related compounds are still used as a first line therapy in the treatment of moderate to severe pain. However, despite the clear benefits of mu agonists in pain management, severe side effects such as dependence and respiratory depression are associated with use of these drugs. To date, there are only two approved mu opioid antagonists for use in the treatment of these adverse effects, that is, naloxone and naltrexone. However, many other clinical and therapeutic areas have been linked to mu opioid receptor antagonism. These include treatment of opioid induced pruritis of the skin, obesity, and Parkinson‐induced tardive dyskinesia. Currently there are two compounds, N‐methylnaltrexone and alvimopan, under FDA review as possible treatments for opioid induced bowel dysfunction and postoperative ileus. These compounds are of special interest as they are peripherally restricted. This attribute enables treatment of peripheral side effects induced by opioid agonists without reversal of the centrally mediated analgesia of the agonist. In this article we discuss the structural classes of mu opioid antagonists, their potential clinical applications, and review the relevant patents of the last ten years.

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Section: Morphinansmentioning

confidence: 99%

Mu Opioid Receptor Antagonists: Recent Developments

2007

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“…Indeed, the ionic bond between the protonated amine and a conserved Asp of the receptor is considered the driving force of the ligand-receptor interaction for all kinds of endogenous opioid peptides [3,5] as well as for exogenous agonists, [6] such as morphine (1) and fentanyls. [7] In most cases, the removal or derivatization of this group resulted in inactive derivatives or antagonists.…”

Section: Introductionmentioning

confidence: 99%

The Inverse Type II β‐Turn on D‐Trp‐Phe, a Pharmacophoric Motif for MOR Agonists

et al. 2011

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Herein we propose the D-Trp-Phe sequence within an inverse type II β-turn as a new kind of pharmacophoric motif for μ-opioid receptor (MOR) cyclopeptide agonists. Initially, we observed that c[Tyr-D-Pro-D-Trp-Phe-Gly] (4), an analogue of endomorphin-1 (H-Tyr-Pro-Trp-Phe-NH₂) lacking the crucial protonatable amino group of Tyr 1, is a MOR agonist with 10⁻⁸ M affinity. Molecular docking analysis suggested that the relevant interactions with the receptor involve D-Trp-Phe. The bioactive conformation of this region was investigated by selected derivatives of 4 designed to adopt an inverse type II β-turn. These efforts led to c[Tyr-Gly-D-Trp-Phe-Gly] (14) and to the cyclotetrapeptide c[D-Asp-1-amide-β-Ala-D-Trp-Phe] (15), showing improved nanomolar affinity. Both 14 and 15 selectively bind MOR, as they have negligible affinity for the κ- and δ-opioid receptors. Both 14 and 15 behave as partial MOR agonists in functional assays. Conformational and docking analyses confirm the role of the inverse β-turn in binding. These results indicate that the D-Trp-Phe inverse β-turn structure can be used for designing non-endomorphin-like peptidomimetic opioid agonists in general, characterized by an atypical mechanism of interaction between ligand and receptor.

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“…In particular, we focused on incorporating an indole or thiazole fragment as the heterocyclic function. Although indole and other heterocycles have been successfully introduced [2,3] at the right side (ring C) of the morphine molecule as the "address" component in the "messageaddress" concept [13,14] resulting in many compounds with interesting pharmacological activities at various opioid receptors, including the well-established d receptor antagonist naltrindole (1) [15] and the k-selective agonist 6'-GNTI (2), [16] fusing such heterocyclic functions to the 14-hydroxymorphinan skeleton has not been well explored. In 1999 and 2007, Coop, Rice, and co-workers [17][18][19] reported a series of compounds by breaking the 4,5-furan ring of naltrindole (1), and found that 14-hydroxyindolomorphinans 3 and 4 with a 4-hydroxy or methoxy group retained reasonable affinity and selectivity for the d receptor.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, most of the opioid receptor ligands currently available originate mainly from alkaloid, morphine, codeine, or thebaine. [2][3][4][5][6] As part of our long-term objective to develop compounds possessing mixed activities at k and m opioid receptors as potential therapeutics for analgesics and treatment for drug abuse, [7][8][9][10][11][12] we recently became interested in the development of 14-hydroxymorphinan analogues characterized by the absence of the 4,5-furan oxygen bridge of morphine and by the incorporation of a heterocyclic functionality at the right side (ring C) of these molecules. In particular, we focused on incorporating an indole or thiazole fragment as the heterocyclic function.…”

Section: Introductionmentioning

confidence: 99%

“…[1] They have served as drug targets of pain and drug abuse for several decades, and a large number of compounds have been generated that target each of these receptors or combinations thereof. [2][3][4] However, the lack of opioid receptor crystal structures and the failure to elucidate the exact 3D orientation of the amino acid residues at the binding sites of these receptors hampered the rational design and development of opioid receptor-selective agents. Therefore, most of the opioid receptor ligands currently available originate mainly from alkaloid, morphine, codeine, or thebaine.…”

Section: Introductionmentioning

confidence: 99%

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[6,7]‐Heterocycle‐Fused 14‐Hydroxymorphinan Derivatives: Design, Synthesis, and Opioid Receptor Activity

Yin

Chen

et al. 2009

ChemMedChem

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A series of new 14-hydroxymorphinan analogues with a thiazole or imidazo[2,1-b]thiazole fragment as the heterocyclic function fused to ring C were designed and synthesized. These compounds can be viewed as the result of a direct modification at ring C of the 14-hydroxymorphinan scaffold. Among these compounds, three were identified as having potent binding affinity (approximately 1 nM) at both kappa and mu receptors, and acting as agonists at kappa and partial agonists or antagonists at mu receptors. In view of the promising results from studies on compounds with mixed kappa and mu receptor activities, these new compounds warrant further investigation.

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Recent advances in selective opioid receptor agonists and antagonists

Cited by 145 publications

References 171 publications

Mu Opioid Receptor Antagonists: Recent Developments

Mu Opioid Receptor Antagonists: Recent Developments

The Inverse Type II β‐Turn on D‐Trp‐Phe, a Pharmacophoric Motif for MOR Agonists

[6,7]‐Heterocycle‐Fused 14‐Hydroxymorphinan Derivatives: Design, Synthesis, and Opioid Receptor Activity

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