Cyclopropane-based conformational restriction of histamine. (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane, a highly selective agonist for the histamine H3 receptor, having a cis-cyclopropane structure.
A series of cyclopropane-based conformationally restricted analogues of histamine, the "folded" cis-analogues, i.e., (1S,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (11), (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (13), and their enantiomers ent-11 and ent-13, and the "extended" trans-analogues, i.e., (1R,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (12) and its enantiomer ent-12, were designed as histamine H(3) receptor agonists. These target compounds were synthesized from the versatile chiral cyclopropane units, (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (14 and 15, respectively) or their enantiomers ent-14 and ent-15. Among the conformationally restricted analogues, the "folded" analogue 13 (AEIC) having the cis-cyclopropane structure was identified as a potent H(3) receptor agonist, which showed a significant binding affinity (K(i) = 1.31 +/- 0.16 nM) and had an agonist effect (EC(50) value of 10 +/- 3 nM) on the receptor. This compound owes its importance to being the first highly selective H(3) receptor agonist to have virtually no effect on the H(4) subtype receptor. These studies showed that the cis-cyclopropane structure is very effective in the conformational restriction of histamine to improve the specific binding to the histamine H(3) receptor.
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Yuji
Y
Kazuta
Kazufumi
K
Hirano
Kentaro
K
Natsume
Shizuo
S
Yamada
Ryohei
R
Kimura
Shun-Ichiro
S
Matsumoto
Kiyoshi
K
Furuichi
Akira
A
Matsuda
Satoshi
S
Shuto
D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C474575:2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane; D003521:Cyclopropanes; D017442:Histamine Agonists; D007093:Imidazoles; D018100:Receptors, Histamine H3