Synthesis of Novel Basic Skeletons Derived from Naltrexone

Nagase, Hiroshi; Fujii, H.

doi:10.1007/128_2010_75

Cited by 19 publications

(6 citation statements)

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“…The Nagase group has identied numerous transformations that reorganize the ring structure of naltrexone in order to enhance the safety and selectivity of naltrexone for specic opioid receptors. 30 From a synthetic standpoint, however, these transformations create dramatically altered products that could be tested for novel biological activity. These include elimination of the D-ring (40) 39 and formation of additional ether rings through a Dring cleaved intermediate (41 and 42).…”

Section: Naltrexonementioning

confidence: 99%

“…Initial investigations focused on the elaboration of NPs for total syntheses or to optimize the activity or selectivity of the original NP through structural modications. 29,30 Recent efforts in this area have formalized this process of multiple structural transformations to produce several highly complex NPs. 31 Application of this method to other NPs should allow for the construction of multiple classes of complex small molecules.…”

Section: Introductionmentioning

confidence: 99%

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Natural products as starting points for the synthesis of complex and diverse compounds

2014

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Covering: up to 2013. Natural products and their derivatives are used as treatments for numerous diseases. Many of these compounds are structurally complex, possessing a high percentage of sp(3) hybridized carbons and multiple stereogenic centers. Due to the difficulties associated with the isolation of large numbers of novel natural products, lead discovery efforts over the last two decades have shifted toward the screening of less structurally complex synthetic compounds. While there have been many success stories from these campaigns, the modulation of certain biological targets (e.g. protein-protein interactions) and disease areas (e.g. antibacterials) often require complex molecules. Thus, there is considerable interest in the development of strategies to construct large collections of compounds that mimic the complexity of natural products. Several of these strategies focus on the conversion of simple starting materials to value-added products and have been reviewed elsewhere. Herein we review the use of natural products as starting points for the generation of complex compounds, discussing both early ad hoc efforts and a more recent systematization of this approach.

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Section: Naltrexonementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Natural products as starting points for the synthesis of complex and diverse compounds

2014

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“…Many KOR agonists, including ethylketocyclazocine, U-50,488H, and nalfurafine (TRK-820), have been developed and investigated for their analgesic, anti-inflammatory and antipruritic activity 5,6) ( Fig. 1).…”

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confidence: 99%

“…11) Although intracerebroventricular pretreatment with an antiserum against dynorphin A (1-17) did not affect the antinociceptive effect induced by subcutaneous (s.c.) treatment of 1 and 2, the antinociceptive effect was greatly attenuated by intrathecal (i.t.) pretreatment with an antiserum against dynorphin A (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) in mice. This suggested that the antinociceptive effect induced by s.c. treatment of 1 and 2 occurred without binding to the KOR in the ventricles of the brain, in where might stimulate the descending dynorphinergic neuron and production of dynorphin in the spinal cord.…”

mentioning

confidence: 99%

“…[12][13][14] We hypothesized that the level of the antinociceptive effect would be affected by the distance between the amide and amino groups, which are important structural components of compound 3. To investigate this, model compounds (4)(5)(6) were designed to study the effect of the spatial relationship between the amide and amine groups on the agonistic activity (Fig. 2).…”

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Design and Synthesis of a Piperidinone Scaffold as an Analgesic through Kappa-Opioid Receptor: Structure–Activity Relationship Study of Matrine Alkaloids

et al. 2016

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The matrine-type alkaloid 4-dimethylamino-1-pentanoylpiperidine (3a) has an antinociceptive effect through its impact on the κ-opioid receptor (KOR). Derivatives of 3a were synthesized by altering its amide and tertiary amine groups, and were evaluated for their antinociceptive effects. The results indicated that the distance between these groups on 3a was optimal for the antinociceptive effect. The effects obtained with compounds 8 and 9 indicated that the relative configuration of the 3-and 4-substituents influenced the effect mediated through the KOR.Key words antinociception; kappa opioid receptor (KOR); matrine; piperidone; acetic acid-induced abdominal contraction test; mouse Narcotic analgesics such as morphine are administered for pain relief to cancer patients. Most narcotic analgesics are µ-opioid receptor (MOR) agonists and have adverse effects such as addiction, 1) respiratory depression, 2) and constipation.3,4) Although stimulation of the κ-opioid receptor (KOR) results in significant analgesia, KOR agonists do not suffer from the same adverse effects as MOR agonists. Many KOR agonists, including ethylketocyclazocine, U-50,488H, and nalfurafine (TRK-820), have been developed and investigated for their analgesic, anti-inflammatory and antipruritic activity 5,6) ( Fig. 1). However, these agonists suffer from dose-limiting dysphoria, sedation, and psychotomimetic effects. 7,8) Consequently, the development of a KOR agonist that does not cause adverse effects is important.We previously reported that (+)-matrine (1) and (+)-allomatrine (2), typical matrine-type lupine alkaloids produced by Sophora Leguminosae, have antinociceptive properties identical to those of pentazocine.9) The effects of 1 were mediated mainly through activation of the KOR and partially through the MOR, and those of 2 were mediated only through the KOR.10) Furthermore, we found that neither 1 nor 2 provided the activation in the guanosine-5′-O-(3-[ 11) Although intracerebroventricular pretreatment with an antiserum against dynorphin A (1-17) did not affect the antinociceptive effect induced by subcutaneous (s.c.) treatment of 1 and 2, the antinociceptive effect was greatly attenuated by intrathecal (i.t.) pretreatment with an antiserum against dynorphin A (1-17) in mice. This suggested that the antinociceptive effect induced by s.c. treatment of 1 and 2 occurred without binding to the KOR in the ventricles of the brain, in where might stimulate the descending dynorphinergic neuron and production of dynorphin in the spinal cord.Because the pharmacological mechanism of action and chemical structures of 1 and 2 differ from conventional KOR agonists, we performed structure-activity relationship (SAR) studies for 1 and 2 and their antinociceptive activity using modifications of the A-D ring systems. The SAR studies showed that the amide group, tertiary amine group, and Cring of 1 and 2 were important in determining their activity. 4-Dimethylamino-1-pentanoylpiperidine (3) was identified as a lead compound through the antinociceptive eff...

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Synthesis of Novel Triplets with a 1,3,5‐Trioxazatriquinane Skeleton and Their Pharmacologies for Opioid Receptors

Nagase

Kutsumura

2015

Archiv der Pharmazie

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We designed and synthesized novel triplet molecules with 1,3,5-trioxazatriquinane skeletons. One class comprises double-capped triplets with a morphinan skeleton; the other class comprises simple phenol derivatives with phenethylamine moieties. One compound with m-phenolic hydroxyl group, called SYK-146, is a highly selective, potent agonist for the κ receptor, with activity nearly equivalent to that of U-50488H. The o-phenolic isomer of SYK-146, called SYK-524, showed potent but non-selective agonistic activity for the opioid receptors. We also added several simple phenol derivatives to a library of compounds that target opioid receptors, and they showed high hit rates for the receptor. This library might also be expected to show high hit rates for other receptors.

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Synthesis of Novel Basic Skeletons Derived from Naltrexone

Cited by 19 publications

References 110 publications

Natural products as starting points for the synthesis of complex and diverse compounds

Natural products as starting points for the synthesis of complex and diverse compounds

Design and Synthesis of a Piperidinone Scaffold as an Analgesic through Kappa-Opioid Receptor: Structure–Activity Relationship Study of Matrine Alkaloids

Synthesis of Novel Triplets with a 1,3,5‐Trioxazatriquinane Skeleton and Their Pharmacologies for Opioid Receptors

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