24 強力な神経興奮作用を示すカイノイドの合成と生理活性(口頭発表の部)

抄録

Kainoids, such as kainic acid, domoic acid, acromelic acids A and B cause marked depolarization against L-glutamate receptor in vertebrate and invertebrate. Due to their potent neuroexcitatory activity, these compounds have been used as useful tools in neuropharmacology. To find the more potent kainoids and reveal the structure-activity relationship, our efforts have been made toward following three syntheses of kainoids and related compounds. (1) Syntheses of acyclic analogues of kainoid.: In these syntheses, we achieved stereoselective syntheses of β-substituted glutamic acids from lactone 9 and lactam 18. (2) Synthesis of acromelic acid families.: We succeeded in the synthesis of acromelic acid families, which had aromatic moiety at C4, by the intramolecular Diels-Alder reaction of 28 as a key step. (3) Synthesis of kainoid.: The most rational synthesis of kainoid, that is, introduction of various substituents to a common intermediate, was achieved by the use of diaryl copper lithium reagent for the substitution reaction of trans-4-tosyloxyproline with retention of configuration. Neuroexcitatory activity of the synthetic compounds was also examined. Among the six acyclic analogues of kainoid, only the (2S,3R) isomers, which have π-electrons on the β-substituent. showed neuroexcitatory activity. In the newly synthesized kainoids, phenyl derivative 43 showed comparable activity to kainic acid. phenol derivative 32 exhibited more potent activity than acromelic acid B or domoic acid, and methoxyphenyl derivative 33 was three-to fivefold potent than acromelic acid A. and the most potent excitatory reagent known so far.