TY - JOUR T1 - Development of<em>trans</em>-2-[1<em>H</em>-Imidazol-4-yl] Cyclopropane Derivatives as New High-Affinity Histamine H<sub>3</sub> Receptor Ligands JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1160 LP - 1168 VL - 289 IS - 2 AU - Clark E. Tedford AU - James G. Phillips AU - Rosilyn Gregory AU - Gary P. Pawlowski AU - Leena Fadnis AU - M. Amin Khan AU - Syed M. Ali AU - Michael K. Handley AU - Stephen L. Yates Y1 - 1999/05/01 UR - http://jpet.aspetjournals.org/content/289/2/1160.abstract N2 - Previously, a novel series of 1H-4-substituted imidazole compounds were described as potent and selective histamine (HA) H3 receptor ligands (Yates et al., 1999). The present studies extend the structure-activity relationships for optimal HA H3 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 H3 receptor with the development of high affinity HA H3 receptor antagonists containing a stereochemical presentation. Structure-activity relationships were established from in vitro HA H3receptor-binding affinities using [3H]Nα-methylhistamine and rat cortical tissue homogenates. Systematic optimization of multiple structural features critical for HA H3 receptor affinity provided some of the most potent HA H3 receptor agents described. For example, GT-2331 was determined to bind to a single population of HA H3 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 &gt; 4 h). In addition, GT-2331 was extremely selective for the HA H3receptor versus other HA receptors and a battery of neurotransmitter, neuropeptide, hormone, or enzyme systems. Several compounds were tested in vitro which suggested HA H3 receptor heterogeneity and are discussed in terms of structure-activity relationships for the HA H3 receptor. The American Society for Pharmacology and Experimental Therapeutics ER -