Design and synthesis of histamine H/H receptor ligands with a cyclopropane scaffold.

We previously designed and synthesized a series of histamine analogues with an imidazolylcyclopropane scaffold and identified potent non-selective antagonists for histamine H and H receptor subtypes. In this study, to develop H selective ligands, we newly designed and synthesized cyclopropane-based derivatives having an indole, benzimidazole, or piperazine structure, which are components of representative H selective antagonists such as JNJ7777120 and JNJ10191584. Among the synthesized derivatives, imidazolylcyclopropanes 12 and 13 conjugated with a benzimidazole showed binding affinity to the H and H receptors comparable to that of a well-known non-selective H/H antagonist, thioperamide. These results suggest that the binding modes of the cyclopropane-based H/H ligands in the H receptor can be different from those of the indole/benzimidazole-piperazine derivatives.