Synthesis of novel 4(5)-(5-aminotetrahydropyran-2-yl)imidazole derivatives and their in vivo release of neuronal histamine measured by brain microdialysis |
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Authors: | Harusawa Shinya Kawamura Makoto Araki Lisa Taniguchi Ryusuke Yoneyama Hiroki Sakamoto Yasuhiko Kaneko Noritsugu Nakao Yumi Hatano Kouta Fujita Takeshi Yamamoto Ryoko Kurihara Takushi Yamatodani Atsushi |
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Institution: | Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan. harusawa@gly.oups.ac.jp |
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Abstract: | The (2R,5S)-trans- and (2S,5S)-cis-stereoisomers 1a and 1b of 4(5)-(5-aminotetrahydropyran-2-yl)imidazole, which have two chiral centers and adopt a stable chair conformation, were synthesized via cyclization of diol intermediates 7 using L-glutamine as the starting material. Their enantiomers, (2S,5R)-trans-1c and (2R,5R)-cis-1d, were synthesized by the same methodology from D-glutamine. Stereo isomers 1a-d were converted into cyanoguanidines 11a-d, and into N-isopropyl and N-3,3-dimethylbutyl derivatives 12a-d and 13a-d, respectively. The results of in vivo brain microdialysis of the derivatives apparently indicated that only (2S,5R)-isomers increased the release of neuronal histamine. Among the many (2S,5R)-N-alkyl derivatives, 13c (OUP-133) and 18 (OUP-153) increased histamine release to 180-190% and 180-200% of basal levels, respectively, and were found to be novel histamine H(3) antagonists. |
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