Synthesis of novel 4(5)-(5-aminotetrahydropyran-2-yl)imidazole derivatives and their in vivo release of neuronal histamine measured by brain microdialysis.
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.
Harusawa
Shinya
S
Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan. harusawa@gly.oups.ac.jp
Kawamura
Makoto
M
Araki
Lisa
L
Taniguchi
Ryusuke
R
Yoneyama
Hiroki
H
Sakamoto
Yasuhiko
Y
Kaneko
Noritsugu
N
Nakao
Yumi
Y
Hatano
Kouta
K
Fujita
Takeshi
T
Yamamoto
Ryoko
R
Kurihara
Takushi
T
Yamatodani
Atsushi
A
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D006632:Histamine / Q000134:cerebrospinal fluid; D006636:Histamine Release / Q000187:drug effects*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D017551:Microdialysis; D008968:Molecular Conformation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011714:Pyrans / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism
C522679:4(5)-(5-aminotetrahydropyran-2-yl)imidazole; D007093:Imidazoles; D007202:Indicators and Reagents; D011714:Pyrans; D006632:Histamine