Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-05-26
2000-11-14
Owens, Amelia
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D31100
Patent
active
061472301
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a novel glutamate receptor agonist, more specifically a novel amino acid dysiherbaine which is an agonist for non-NMDA type glutamate receptors as well as salts and biological precursors thereof.
PRIOR ART
L-glutamic acid has attracted attention as an excitatory neurotransmitter in central nervous systems of mammals, a neuroexcitotoxin which destroys neurocytes to cause various cerebro-neuropathies, and a substance which has an important role in the formation of memory or learning.
L-glutamate receptors are associated with such a variety of physiological functions and classified into two types, i.e. ionotropic receptors (iGluR) and metabotropic receptors (mGluR). Ionotropic receptors are subclassified based on the recent information on exogenous agonists into the following three subtypes: AMPA=.alpha.-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and these abbreviations will be hereinafter sometimes used.
KA type and AMPA type are sometimes collectively called as non-NMDA type.
Among non-NMDA type receptors, KA type receptors are thought to be involved in neuronal death since it has been found that kainic acid itself induces epileptoid lesions and neuronal degeneration in rats. On the other hand, AMPA receptors are considered to be involved in normal rapid transmission in central nervous systems and the activation of AMPA receptors seem to trigger the activation of NMDA type receptors. In recent years, researches on the level of molecular biology have showed that ionotropic L-glutamate receptors types 1-4 (iGluR 1-4) correspond to receptors of AMPA type while types 5-7 (iGluR 5-7) and types KA1, 2 correspond to receptors of KA type.
SUMMARY OF THE INVENTION
As described above, stimulation of glutamate receptors by L-glutamic acid plays an important role in living bodies, including neuronal death and the signal transduction of the central nervous system. Thus, glutamate receptor agonists are experimental materials indispensable for explaining the functions of the nervous system. However, the only known agonists for non-NMDA type (particularly KA type) receptors are kainoids (collective name of the compounds which have a kainic acid skeleton in their molecule) such as naturally occurring domoic acid and acromelic acid. Therefore, there is a demand for development of agonists/antagonists with a new skeleton for use in investigations of the functions of the receptors.
DETAILED DESCRIPTION OF THE INVENTION
Bearing in mind that a number of natural marine products known as poisons can act at micro-doses on systems which are involved in intracellular/intercellular signal transduction, we have made an attempt to isolate a novel compound with a specific physiological activity. As a result, we found that an aqueous extract of a species of Micronesian sponge (Dysidea herbacea) induces characteristic conditions such as paroxysmal spasm in mice.
As a result of careful studies to isolate and purify the active substance inducing these conditions on the basis of the above finding, we have succeeded in isolating a novel amino acid represented by the following chemical formula (1): ##STR2## from an aqueous extract of D. herbacea on the basis of toxicity to mice by combining liquid chromatography and high performance liquid chromatography (HPLC). The compound of this structure is an agonist for non-NMDA type glutamate receptors, and named dysiherbaine.
The compound of the chemical formula (1) in the form of a salt or a biological precursor in which one or each of two carboxyl groups forms a lower alkyl ester, for example, will be converted in vivo into dysiherbaine and also shows its biological activity.
Accordingly, the present invention provides a novel amino acid dysiherbaine as well as salts and biological precursors thereof as agonists for non-NMDA type glutamate receptors.
Examples of lower alkyl esters of the compound of the present invention include esters with a straight or branched lower alkyl group containing 1 to 5 carbon atoms, such as methyl
REFERENCES:
patent: 4959493 (1990-09-01), Ohfume et al.
J. Am. Chem. Soc. 1997, 119, 4112-4116, Ryuichi Sakai et al., "Dysiherbaine: A New Neurotoxic Amino Acid from the Micronesian Marine Sponge Dysidea Herbacea"
Kamiya Hisao
Murata Michio
Sakai Ryuichi
Shimamoto Keiko
Owens Amelia
Suntory Limited
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