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 described as potent and selective histamine (HA) H-3 receptor ligands (Yates et al., 1999). The present studies extend the structure-activity relationships for optimal HA H-3 receptor affinity and central nervous system penetration 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 HA H-3 receptor antagonists containing a stereochemical presentation. Structure-activity relationships were established from in vitro HA H-3 receptor-binding affinities using [H-3]N-alpha-methylhistamine and rat cortical tissue homogenates. Systematic optimization of multiple structural features critical for HA H-3 receptor affinity provided some of the most potent HA H-3 receptor 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-2331 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, hormone, or enzyme systems. Several compounds were tested in vitro which suggested HA H-3 receptor heterogeneity and are discussed in terms of structure-activity relationships for the HA H-3 receptor.