Development of trans-2-[lH-imidazol-4-yl] cyclopropane derivatives as new high-affinity histamine H-3 receptor ligands

Previously, a novel series of 1H-4-substituted imidazole compounds were des cribed as potent and selective histamine (HA) H-3 receptor ligands (Yates e t al., 1999). The present studies extend the structure-activity relationshi ps for optimal HA H-3 receptor affinity and central nervous system penetrat ion by incorporation of a conformationally restricted cyclopropane nucleus. Moreover, the current studies extend our understanding of ligand-receptor interactions at the HA H-3 receptor with the development of high affinity H A H-3 receptor antagonists containing a stereochemical presentation. Struct ure-activity relationships were established from in vitro HA H-3 receptor-b inding affinities using [H-3]N-alpha-methylhistamine and rat cortical tissu e homogenates. Systematic optimization of multiple structural features crit ical for HA H-3 receptor affinity provided some of the most potent HA H-3 r eceptor agents described. For example, GT-2331 was determined to bind to a single population of HA H-3 receptors with a K-i of 0.125 nM. In vivo, GT-2 331 has a favorable central nervous system penetration profile with an ED50 of 0.08 mg/kg (i.p.) in rats and a long duration of action (T-1/2 > 4 h). In addition, GT-2331 was extremely selective for the HA H-3 receptor versus other HA receptors and a battery of neurotransmitter, neuropeptide, hormon e, or enzyme systems. Several compounds were tested in vitro which suggeste d HA H-3 receptor heterogeneity and are discussed in terms of structure-act ivity relationships for the HA H-3 receptor.