title: The role of HB-donor groups in the heterocyclic polar fragment of H3-antagonists. I. Synthesis and biological assays.
abstract: It has been recently reported that compounds composed of an imidazole connected through an alkyl spacer to a 2-aminobenzimidazole showed high affinity towards the H(3)-receptor. The guanidine fragment of the 2-aminobenzimidazole is probably involved in hydrogen bond interactions at the binding site, and is referred to as the 'polar fragment'. In the present work, starting from 2-aminobenzimidazole derivatives with a di-methylene spacer 1 (pK(i)=7.25) or a tri-methylene one 2 (pK(i)=8.90), we investigated the importance of the hydrogen bond (HB) donor groups at the polar fragment in the interaction with the H(3)-receptor. The replacement of 2-aminobenzimidazoles with different moieties [2-aminobenzothiazole, 3, 4; 2-thiobenzimidazole, 5, 6; 2-thiobenzothiazole, 7, 8; 2-thio-4-phenyl- or 2-thio-5-phenyl-N-methylimidazoles, 9-12] highlighted the effect of the polar group basicity on the optimal length of the alkyl chain: longer spacers were preferred with polar groups of moderate basicity whereas, in the presence of neutral polar groups, the best affinity values were obtained with di-methylene chains. Moreover, N-methylation at the 2-aminobenzimidazole moiety 13-16 revealed different behaviour for compounds having different spacer lengths. In fact, methylation of the exocyclic NH group maintained high affinity for the tri-methylene 2-aminobenzimidazole derivative, while a drop in affinity was observed for the annular N-methylation. An opposite trend characterised di-methylene derivatives. These observed SAR suggest that, within this class of compounds, the number of HB-donor groups can be lowered while maintaining high receptor affinity. Since the presence of HB-donor groups strongly affects brain access, this observation could be useful to design and prepare new H(3)-antagonists.
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D001681:Biological Assay; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D006860:Hydrogen Bonding; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D006571:Heterocyclic Compounds; D006633:Histamine Antagonists; D018100:Receptors, Histamine H3