25 脳内中枢型IP2受容体高親和性PGの創製と生物活性(口頭発表の部)

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The role of prostacyclin (PGI_2, 1) in the central nervous system (CNS) has still been unclear because of the lack of a specific ligand for a PGI_2 receptor in CNS. In this context, we recently elaborated 15R-TIC (2) with high binding affinity and selectivity for novel IP2 receptor which is specifically expressed in CNS neurons. The R configuration of the hydroxy-bearing C(15) in 2 is fascinating, because, in general, the configuration of biological active PGs at C(15) position is known to be S. In this symposium, we describe synthesis of the TIC derivatives for structure-binding affinity relationship in addition to biological actions. In consequence, 15-deoxy-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin (5) (referred to as 15-deoxy-TIC) exhibited, among others, highest binding affinity and selectivity for a IP2 receptor. 5 has been prepared based on the combination of the Witting reaction and Pd(0)-mediated coupling of an allyl carbonate and a sulfone. Thus, Witting reaction of aldehyde 7 and a phosphorane led to 8. The reduction of 8 and subsequent methoxy carbonylation gave allyl carbonate 9 which was treated with disulfone 10 in the presence of a 1: 1 mixture of Pd(0) and diphenylphosphinoethane to give 11. Reductive removal of phenyl sulfonyl groups of 11 and subsequent deprotection of THP group gave methyl ester 12. Finally, alkaline hydrolysis of 12 led to 5. 2 and 5 prevented apoptotic cell death of hippocampal neurons induced under high oxygen (50%) atmosphere. 6, isocarabacyclin, and natural PGs except for 1 did not show such a biological effect.
天然有機化合物討論会の論文
1998-08-31

25 脳内中枢型IP2受容体高親和性PGの創製と生物活性(口頭発表の部)

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