41 中枢神経系プロスタサイクリン受容体探索分子の設計・合成および活用(口頭発表の部)

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Recently, the role of prostaglandins (PGs) in brain function has attracted much attention. We succeeded in creating a stable ligand with high binding affinity and selectivity for a prostacyclin (1, PGI_2) receptor expressed in the central nervous system (CNS). The ligand, (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin (3, 15R-TIC), was prepared starting from the Horner-Emmons reaction of aldehyde 4 and β-keto phosphonate 5 followed by 1,2-reduction of the enone, separation of the resulting C(15)-epimers, and hydrolysis of the methyl ester. The binding assay was conducted by the [^3H]isocarbacyclin displacement study using the rat frozen tissue sections containing the thalamus or NTS (nucleus tractus solitarius) as representative of the CNS or peripheral nervous system. Consequently, 3 exhibited high binding affinity sufficient for a receptor in the thalamus (IP_2) but showed very weak binding for a receptor in the NTS (IP_1). In contrast, cicaprost (12), a stable PGI_2 agonist belonging to an iloprost family, showed high binding affinity and selectivity for IP_1. 15S-TIC (9), the C(15)-epimer of 3, and isocarbacyclin (2) bound strongly with both of the receptors. Electrophysiological studies carried out in the CA1 region of the rat hippocampus revealed that the PGI_2 analogs have a facilitatory effect on the excitatory transmission through IP_2. The widespread expression of IP_2 in the CNS suggests that PGI_2 has important roles in neuronal activity. In order to identify IP_2, we prepared an azido-functionalized isocarbacyclin derivative 14 as a photoaffinity probe, which showed strong binding affinity for IP_2.
1996-09-02

41 中枢神経系プロスタサイクリン受容体探索分子の設計・合成および活用(口頭発表の部)

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