Investigation of the bioactive conformation of histamine H3 receptor antagonists by the cyclopropylic strain-based conformational restriction strategy.

We previously identified the highly potent histamine H(3) receptor antagonists (1R,2S)-2-[2-(4-chlorobenzylamino)ethyl]-1-(1H-imidazol-4-yl)cyclopropane (1) and its enantiomer ent-1. Although the conformations of 1 and ent-1 are restricted by the central cyclopropane ring, the 2-(4-chlorobenzylamino)ethyl side chain essential for the H(3) receptor binding may somewhat freely rotate. To investigate the bioactive conformation, the 1'-ethyl-substituted derivatives 2a and 2b and their enantiomers ent-2a and ent-2b were designed as side chain conformation-restricted analogues of 1 and ent-1, based on the cyclopropylic strain. These compounds were synthesized, and their analysis by NMR and calculations suggested that the side chain moiety was effectively restricted in a syn-form or an anti-form by the cyclopropylic strain as expected. Pharmacological evaluation and docking simulation showed that the bioactive conformations of 1 and ent-1 appear to be the syn-form and the anti-form, respectively. Thus, the cyclopropylic strain can be effectively used for conformational restriction of the side chain moiety of cyclopropane compounds.