Acromelic Acid Research Articles

Enantioselective total synthesis of (-)-kainic acid and (+)-acromelic acid C via Rh(i)-catalyzed asymmetric enyne cycloisomerization.

A diversity-oriented synthetic strategy was developed for the total synthesis of kainoid amino acids, which led to the enantioselective synthesis of (-)-kainic acid and the first total synthesis of (+)-acromelic acid C. Rh(i)-catalyzed asymmetric enyne cycloisomerization served as the key reaction in this strategy for the rapid construction of highly functionalized lactam, and the resulting vinyl acetate moiety was further utilized as a versatile building block for the installation of both isopropylidene and 2-pyridone units existing in natural kainoids.

Comparison of mechanisms of allodynia induced by acromelic acid A between early and late phases

We previously showed that intrathecal administration of acromelic acid A (ACRO-A) provoked tactile allodynia in mice. As well, recent studies have demonstrated that the activation of NMDA glutamate receptor-neuronal nitric oxide synthase (nNOS) pathway and glia play crucial roles in the development and maintenance of neuropathic pain. In order to clarify their involvement in ACRO-A-induced allodynia, we investigated the effects of various agents on two mouse models at early and late-phase allodynia. The agents employed were Ca2+ channel α2δ ligands, NMDA and AMPA receptor antagonists, nNOS, and Ca2+/calmodulin kinase II inhibitors. When injected simultaneously with ACRO-A, all of these agents blocked allodynia in the early-phase group; however, they did not block allodynia when injected 7 days after the administration of ACRO-A in the late-phase group. In order to block glial activation, astrocytic inhibitor L-α-aminoadipate (LAA) or microglial inhibitor minocycline was administrated, and allodynia was examined on day 7. Activations of nNOS and glia in the spinal cord were histochemically examined at 1h or 1 week after injection of ACRO-A. We found that nNOS activity increased 1h after ACRO-A injection; however, it did not increase 1 week after ACRO-A injection. Conversely, microglial activation was observed 1 week after ACRO-A injection and was significantly inhibited with minocycline treatment. Moreover, only LAA was found to inhibit late-phase allodynia.In this study, we demonstrate that NMDA receptor activation is involved only in ACRO-A-induced tactile allodynia in the early phase, and that spinal astrocytic activation contributes to allodynia in the late phase.

Pregabalin beneficial effects on sleep quality or health-related quality of life are poorly correlated with reduction on pain intensity

Pregabalin beneficial effects on sleep quality or health-related quality of life are poorly correlated with reduction on pain intensity

The action site of the synthetic kainoid (2S,3R,4R)-3-carboxymethyl-4-(4-methylphenylthio)pyrrolidine-2-carboxylic acid (PSPA-4), an analogue of Japanese mushroom poison acromelic acid, for allodynia (tactile pain)

We previously demonstrated that intrathecal (i.t.) administration of acromelic acid A (Acro-A) induced allodynia in mice and that simultaneous administration of (2S,3R,4R)-3-carboxymethyl-4-(phenylthio)pyrrolidine-2-carboxylic acid (PSPA-1), an Acro-A analogue, attenuated the Acro-A-induced allodynia. To clarify a mechanism of PSPA-1, we attached methyl radical to PSPA-1 and synthesized (2S,3R,4R)-3-carboxymethyl-4-(4-methylphenylthio) pyrrolidine-2-carboxylic acid (PSPA-4) and [11C]PSPA-4 for behavioral and autoradiography studies. Although PSPA-4 inhibited the Acro-A-induced allodynia in a dose-dependent manner from 1 to 10fg/mouse, PSPA-4 itself induced allodynia at 10 to 100pg/mouse. In vitro autoradiography, [11C]PSPA-4 was specifically bound to the rat brain and spinal cord, and the binding was significantly displaced by PSPA-1 and kainic acid, but not by AMPA and antagonists of NMDA, AMPA and kainate receptors. Conversely, [3H]kainate was specifically bound to the rat brain and the dorsal horn of spinal cord, and the binding was significantly displaced by PSPA-1 and PSPA-4. The PSPA-4-induced allodynia was blocked by the AMPA/kainate antagonist GYKI53655, but not by kainate antagonists NS102 and UBP296. PSPA-4 increased intracellular Ca2+ concentration in 27.9% of cultured dorsal root ganglion neurons responding to glutamate, much higher than kainate in 10.9% of them. Taken together, these results suggest that PSPA-4 attenuated the Acro-A-induced allodynia at low doses and induced allodynia at high doses via a binding site different from known kainate antagonists. The development of a radio-labeled PSPA-4 will enable us to promote the understanding of the action mechanism not only of Acro-A, but also of pain transmission in the periphery and central nervous system.

Synthesis of an acromelic acid A analog-based 11C-labeled PET tracer for exploration of the site of action of acromelic acid A in allodynia induction

A novel (11)C-labeled PET (positron emission tomography) tracer, which was designed based on the (phenylthio)pyrrolidine derivative that can competitively block the acromelic acid A-induced allodynia, was synthesized. A protocol in which methylation by palladium-mediated coupling of the boronate derivative with [(11)C]CH(3)I and deprotection of the protected amino acid moiety are successively performed in one-pot within 5 min was established for the synthesis of the tracer. The tracer is potentially useful as a tool to investigate the mode of action of acromelic acid A in the induction of allodynia.

Excitatory actions of mushroom poison (acromelic acid) on unmyelinated muscular afferents in the rat

Ingestion of a poisonous mushroom, Clitocybe acromelalga, results in strong and long-lasting allodynia, burning pain, redness and swelling in the periphery of the body. Acromelic acid (ACRO), a kainate analogue isolated from the mushroom, is assumed to be involved in the poisoning. ACRO has two isomers, ACRO-A and ACRO-B. The potency of ACRO-A is a million times higher than that of ACRO-B for induction of allodynia when intrathecally administered in mice. The effect of ACRO on the primary afferents of somatic tissues remains largely unknown. The aim of the present study was to examine the effect of ACRO-A on the response behavior of unmyelinated afferents in the skeletal muscle. For this purpose single fiber recordings of C-afferents were made from rat extensor digitorum longus (EDL) muscle-common peroneal nerve preparations in vitro. Intramuscular injections of ACRO-A at three different concentrations (10 −12, 10 −10 and 10 −8 M, 5 μl over 5 s) near the receptive field in the EDL muscle elicited excitation of C-afferents (12%, 50% and 44%, respectively). ACRO-A at the concentration of 10 −10 M induced the strongest excitation. The incidence of ACRO-A responsive fibers at the concentration of 10 −10 and 10 −8 M was significantly higher than that at 10 −12 M. The responses to mechanical and heat stimulations did not differ between ACRO-A sensitive and insensitive fibers. These results clearly demonstrated the powerful excitatory action of ACRO-A on mechanosensitive unmyelinated afferents in the rat skeletal muscle.

Synthesis of a Bis‐Azido Analogue of Acromelic Acid for Radioisotope‐Free Photoaffinity Labeling and Biochemical Studies.

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Synthesis of a bis-azido analogue of acromelic acid for radioisotope-free photoaffinity labeling and biochemical studies

A novel acromelic acid analogue containing a phenyl group possessing two different types of azido functional groups, of which one is the aromatic N 3 acting as a photoaffinity group to bind to a target protein by photoirradiation and the other is alkyl N 3 group which survives photolysis acting as a detecting group through the Staudinger–Bertozzi reaction to identify the ligated product, was designed and synthesized as a radioisotope-free biochemical probe potentially for studies on kainoid receptors.

Mass spectrometric determination of acromelic acid A from a new poisonous mushroom: Clitocybe amoenolens

As Clitocybe acromelalga, the mushroom Clitocybe amoenolens is responsible for erythermalgia. Acromelic acids isolated from C. acromelalga have been suspected to be to some extend the active principles. The objective was to develop a specific and sensitive liquid chromatographic–mass spectrometric method that would allow acromelic acid A identification and quantification in mushrooms. The method involved a single-step methanol–water extraction followed by a selective cleanup of the extract with solid-phase extraction cartridges (strong-anion exchange). The chromatographic separation was achieved on a porous graphitic carbon column with acetonitrile–water–formic acid as mobile phase. Detection was done with a mass analyzer equipped with a TurboIonSpray ® source, operated in the negative ionization mode. Acromelic acid A concentration was determined in dried mushroom at around 325 ng/mg in C. amoenolens and 283 ng/mg in C. acromelalga.

A simple acromelic acid analog potentially useful for receptor photoaffinity labeling and biochemical studies

A novel acromelic acid analog possessing an azido-functionalized phenyl group was designed and synthesized as a biochemical probe for studies on kainoid receptors. The analog exerted a biological activity equivalent to natural acromelic acid A, suggesting that both compounds possibly bind to the same target biomolecule. In order to utilize the probe in photoaffinity labeling experiments, a procedure for the introduction of radioactive iodine into the molecule was established.

Using the COSYMA System for the Discovery of Synthesis Strategies by Analogy

AbstractCOSYMA is a computer program whose use is to suggest synthesis strategies for complex organic molecules. During a learning stage, which has been presented in previous papers, strategies (sequences of key reaction steps) are automatically extracted from total syntheses, described in the literature, and stored in a knowledge base. This paper presents the storage of strategies and the use of COSYMA to solve synthetic problems: how strategies applicable to a submitted target molecule are selected, and “instanciated” according to the structural specificities of this target. We provide an example of using COSYMA for discovering synthesis strategies for acromelic acid. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

A New Synthetic Method for an Acromelic Acid Analogue, a Potent Neuroexcitatory Kainoid Amino Acid, via Photoinduced Benzyl Radical Cyclization.

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A new synthetic method for an acromelic acid analog, a potent neuroexcitatory kainoid amino acid, via photoinduced benzyl radical cyclization

A new synthetic method for an acromelic acid analog, MFPA, was developed. The key step is the photoinduced benzyl radical cyclization with excellent stereoselectivity.

Dearomatising cyclisation of lithiated 1-naphthamides with a phenylglycinol-derived chiral auxiliary: asymmetric synthesis of an arylkainoid and a kainoid-like pyroglutamate

1-Naphthamides of N-benzylphenylglycinols undergo a diastereoselective dearomatising cyclisation on treatment with t-BuLi and DMPU or HMPA. A new pyrrolidinone ring is formed bearing three new stereogenic centers of defined absolute stereochemistry. Removal of the phenylglycinol auxiliary gives enantiomerically pure substituted lactams exhibiting the stereochemistry of the kainoids. These may be converted to kainoid-like pyroglutamates, or alternatively, using the method of the previous paper, to analogues of acromelic acid.

Parallel synthesis of novel heteroaromatic acromelic acid analogues from kainic acid.

A range of new C-4 heteroaromatic acromelic acid analogues has been synthesized in a parallel fashion from (-)-alpha-kainic acid 1. Protection of the amine and carboxylate groups of 1 followed by ozonolysis gave methyl ketone 8. A silyl enol ether 9, generated regiospecifically from the methyl ketone 8 using "kinetic" conditions, was brominated in situ with phenyltrimethylammonium perbromide to give the key alpha-bromo ketone 10. Parallel cyclization reactions of bromo ketone 10 with thioamides and thioureas were then performed. The aromatic heterocyclic derivatives 11a-d and 19 produced were deprotected to give the new kainoid amino acids 6a-d and 25 in excellent yield. Compounds 6a and 6c show strong binding to the kainate receptor. Reaction of 10 with alternative condensing agents was also briefly investigated.

Pharmacology of the glutamate receptor

The history of pharmacological examinations of glutamate receptor agonists such as kainic acid, quisqualic acid, acromelic acid, L-CCG-I, DCG-IV and L-F2CCG-I was described. Kainic acid is one of the most potent excitants in the mammalian central neurons, and its powerful excitatory actions gave rise to the excitotoxic concept that glutamate destroys neurons by excessive activation of excitatory receptors. Single systemic administration of acromelic acid, a kainate analog, caused behavioral and pathological effects quite different from those seen after systemic administration of kainate in the rat, demonstrating that the distribution of neuron damage caused by various excitatory amino acids is not always identical even if their receptors are in the same pharmacological category. 2-(Carboxycyclopropyl)glycine (CCG) is a conformationally restricted analogue of glutamate. CCG and its derivatives demonstrate unique neuropharmacological actions; for example, L-CCG-I and DCG-IV (a carboxylated derivative of L-CCG-I) relatively preferentially activate group II mGluRs. Prolonged infusion of very small amounts of DCG-IV showed a bell-shaped dose-response relationship with regard to protection against kainate-induced neurotoxicity. Low concentrations of L-glutamate neither affected spinal reflexes nor the resting membrane potentials of motoneurons, but preferentially potentiated the depression of monosynaptic excitation caused by L-F2CCG-I. Following L-F2 CCG-I treatment, L-glutamate decreased the monosynaptic spinal reflexes in a concentration-dependent manner, indicating a 'priming' effect of L-F2CCG-I. Thus, pharmacological actions of mGluR agonists are of great interest and remain to be clarified.

ChemInform Abstract: A Biomimetic Approach to the Pyridone Rings of the Acromelic Acids: A Concise Synthesis of Acromelic Acid A and an Approach to Acromelic Acid B.

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A biomimetic approach to the pyridone rings of the acromelic acids: A concise synthesis of acromelic acid A and an approach to acromelic acid B

The syntheses of acromelic acid A 1, allo-acromelic acid A 19 and an approach towards acromelic acid B 2 are described. Palladium (0) catalysed cross-coupling reactions were used to generate C-4 catechol precursors and formation of the pyridone rings was investigated using a biomimetic oxidative cleavage - recyclisation strategy.

Concise syntheses of acromelic acid A and allo-acromelic acid A

Acromelic acid A 1 and allo-acromelic acid A 12 were synthesised in a biomimetic fashion. An oxidative cleavage - recyclisation strategy was used to construct the requisite C-4 pyridone from an intermediate catechol.

Towards a versatile synthesis of kainoids I: Introduction of the C-3 and C-4 substituents

The first stages in the synthesis of acromelic acid analogues from trans-4-hydroxy-L-proline are described. An enamine alkylation was used to stereospecifically introduce the C-3 substituent, Grignard addition to a ketone or Pd(0) catalysed cross-coupling procedures adding C-4 aryl substituents for further manipulation. A number of versatile intermediates were generated.