The structure of paraherquamide, a toxic metabolite from

Yamazaki, Mikio; Okuyama, Emi; Kobayashi, Makoto; Inoue, Hironao

doi:10.1016/0040-4039(81)80168-2

Cited by 201 publications

(96 citation statements)

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“…1) is a novel anthelmintic (Yamazaki et al, 1981) that is an alkaloid fermentation product originally isolated from Penicillium paraherquii. The anthelmintic property of paraherquamide was first identified using jirds infected with Trichostrongylus colubriformis (Ostlind et al, 1990).…”

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confidence: 99%

Paraherquamide and 2-Deoxy-paraherquamide Distinguish Cholinergic Receptor Subtypes in Ascaris Muscle

Robertson¹,

Clark²,

Burns³

et al. 2002

J Pharmacol Exp Ther

114

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Paraherquamide is a novel natural anthelmintic product with a mode of action that is incompletely characterized. Nicotine and cholinergic-anthelmintic agonists of different chemical classes were used to produce contraction in Ascaris muscle strips. Paraherquamide and a semisynthetic derivative, 2-deoxy-paraherquamide, antagonized these responses. Analysis of the actions of the antagonists was made using the simple competitive model and nonlinear regression to estimate the pK B values of the antagonists. The analysis was tested using Clark plots. The pK B values for paraherquamide were: nicotine, 5.86 Ϯ 0.14; levamisole, 6.61 Ϯ 0.19; pyrantel, 6.50 Ϯ 0.11; and bephenium, 6.75 Ϯ 0.15. The pK B of nicotine was significantly different from the pK B values for levamisole, pyrantel, and bephenium, showing that paraherquamide can distinguish a subtype of cholinergic receptors sensitive to nicotine and a subtype of cholinergic receptors sensitive to levamisole, pyrantel, and bephenium. The pK B values for 2-deoxy-paraherquamide were: levamisole, 5.31 Ϯ 0.13; pyrantel, 5.63 Ϯ 0.10; and bephenium, 6.07 Ϯ 0.13. The Clark plots of the antagonism illustrated the degree of fit to the competitive model for 2-deoxy-paraherquamide. 2-Deoxy-paraherquamide selectively antagonized the effects of bephenium; the pK B values of levamisole and pyrantel were significantly different from the pK B of bephenium. Paraherquamide and 2-deoxy-paraherquamide are selective competitive cholinergic antagonists that distinguish subtypes of cholinergic receptor in Ascaris muscle corresponding to nicotine-, levamisole-, and bephenium-sensitive receptors.Nematode parasite infections of humans and animals cause disease with loss of productivity, debility, and occasionally death. Ascariasis and hookworm infections are carried by 1.6 billion people throughout the world and in 2% of cases cause loss of life. The use of therapeutic compounds forms a major component of control, and the development of novel therapeutic agents is required to deal with the increasing levels of resistance to existing drugs.Paraherquamide (Fig. 1) is a novel anthelmintic (Yamazaki et al., 1981) that is an alkaloid fermentation product originally isolated from Penicillium paraherquii. The anthelmintic property of paraherquamide was first identified using jirds infected with Trichostrongylus colubriformis (Ostlind et al., 1990). Paraherquamide produces paralysis of parasitic nematodes in culture, without an effect on ATP, suggesting that it does not act as a metabolic poison (Thompson et al., 1996). Interestingly, one of the toxic effects of paraherquamide in the dog (Shoop et al., 1990) is a prolapsed nictitating membrane, an effect that suggests antagonism of neuronal nicotinic receptors (nAChRs). Recently, it has been reported (E.

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mentioning

confidence: 99%

Paraherquamide and 2-Deoxy-paraherquamide Distinguish Cholinergic Receptor Subtypes in Ascaris Muscle

Robertson¹,

Clark²,

Burns³

et al. 2002

J Pharmacol Exp Ther

114

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“…[1] Examples include the mycotoxin paraherquamide 1, [2] the potent proteasome inhibitor marine product salinosporamide A 2 [3] and the glutamate receptor agonist kainic acid 3 ( Figure 1). [4] Figure 1.…”

Section: Stereoselective Synthesis Of Functionalized Pyrrolidines By mentioning

confidence: 99%

Stereoselective Synthesis of Functionalized Pyrrolidines by the Diverted N−H Insertion Reaction of Metallocarbenes with β‐Aminoketone Derivatives

et al. 2016

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A highly stereoselective route to functionalized pyrrolidines by the metal‐catalyzed diverted N−H insertion of a range of diazocarbonyl compounds with β‐aminoketone derivatives is described. A number of catalysts (rhodium(II) carboxylate dimers, copper(I) triflate, and an iron(III) porphyrin) are shown to promote the process under mild conditions to give a wide range of highly substituted proline derivatives. The reaction starts as a metallocarbene N−H insertion but is diverted by an intermolecular aldol reaction.

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Section: A Note On Versionsmentioning

confidence: 99%

Stereoselective Synthesis of Functionalized Pyrrolidines by the Diverted N−H Insertion Reaction of Metallocarbenes with β‐Aminoketone Derivatives

et al. 2016

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A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. Abstract: A highly stereoselective route to functionalized pyrrolidines from the metal catalyzed diverted N-H insertion of a range of diazocarbonyl compounds with β-aminoketone derivatives is described. A number of catalysts (rhodium(II) carboxylate dimers, copper(I) triflate and an iron(III)porphyrin) are shown to promote the process under mild conditions to give a wide range of highly substituted proline derivatives. The reaction starts with a metallocarbene N-H insertion but is diverted by an intermolecular aldol reaction.Amongst N-heterocyclic compounds of biological relevance, pyrrolidines are among the most important, and feature in a large number of naturally occurring and unnatural compounds. [1] Examples include the mycotoxin paraherquamide 1, [2] the potent proteasome inhibitor marine product salinosporamide A 2 [3] and the glutamate receptor agonist kainic acid 3 (Figure 1). [4]

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The structure of paraherquamide, a toxic metabolite from

Cited by 201 publications

References 1 publication

Paraherquamide and 2-Deoxy-paraherquamide Distinguish Cholinergic Receptor Subtypes in Ascaris Muscle

Paraherquamide and 2-Deoxy-paraherquamide Distinguish Cholinergic Receptor Subtypes in Ascaris Muscle

Stereoselective Synthesis of Functionalized Pyrrolidines by the Diverted N−H Insertion Reaction of Metallocarbenes with β‐Aminoketone Derivatives

Stereoselective Synthesis of Functionalized Pyrrolidines by the Diverted N−H Insertion Reaction of Metallocarbenes with β‐Aminoketone Derivatives

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