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

Abstract

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 H₃ 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 H₃ receptor agonist, which showed a significant binding affinity (K_i = 1.31 ± 0.16 nM) and had an agonist effect (EC₅₀ value of 10 ± 3 nM) on the receptor. This compound owes its importance to being the first highly selective H₃ receptor agonist to have virtually no effect on the H₄ 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 H₃ receptor.