On the other hand imidazolylcyclopropane
On the other hand, imidazolylcyclopropane derivatives and having a 2-substituted benzimidazolyl group showed moderate binding affinities for both the HR and HR. Replacement of 4-chlororbenzylamino group of with a benzimidazolyl group () led to increase the affinity for the HR more than 5-fold ( = 186 nM for ; >1,000 nM for ), whereas the replacement did not significantly affect the HR affinity ( = 295 nM for ; 118 nM for ). Notably, the values of , which have a benzimidazolyl group instead of 4-chlorophenyl group of , to the HR (52 nM) and the HR (166 nM) were comparable to those tgf beta receptor of a well-known non-selective H/H antagonist, thioperamide (H, 51 nM; H, 124 nM; its structure is shown in ), although their values were bigger than those of (H, 8.4 nM; H, 7.6 nM). The indole/benzimidazole-piperazine derivatives and are the highly HR selective antagonists; however, this series of -cyclopropane derivatives – with an indole, benzimidazole, or piperazine structure did not show the HR selectivity.
In summary, to develop newly HR selective ligands, we hybridized our cyclopropane-based conformationally restricted histamine analogues with indole/benzimidazole-piperazine derivatives, which are representative H selective antagonists. Whereas most of the synthesized derivatives showed no binding affinities for both the HR and HR, compound showed the H/H binding affinities comparable to thioperamide. The present study suggests that the binding modes of the cyclopropane-based ligands in the HR might be entirely different from those of the indole/benzimidazole-piperazine derivatives.