Dibasic non-imidazole histamine H3 receptor antagonists with a rigid biphenyl scaffold.

Abstract A class of rigid, dibasic, non-imidazole H 3 antagonists was developed, starting from a series of previously described flexible compounds. The original polymethylene chain between two tertiary amine groups was replaced by a rigid scaffold, composed by a phenyl ring or a biphenyl fragment. Modulation of the distance between the two amine groups, and of their alkyl substituents, was driven by superposition of molecular models and docking into a receptor model, resulting in the identification of 1,1′-[biphenyl-4,4′-diylbis(methylene)]bis-piperidine ( 5 ) as a subtype-selective H 3 antagonist with high binding affinity (p K i  = 9.47) at human H 3 histamine receptor.