RT Journal Article SR Electronic T1 Identification and Pharmacological Characterization of a Series of New 1H-4-Substituted-Imidazoyl Histamine H3 Receptor Ligands JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1151 OP 1159 VO 289 IS 2 A1 Stephen L. Yates A1 James G. Phillips A1 Rosilyn Gregory A1 Gary P. Pawlowski A1 Leena Fadnis A1 M. Amin Khan A1 Syed M. Ali A1 Clark E. Tedford YR 1999 UL http://jpet.aspetjournals.org/content/289/2/1151.abstract AB A new series of 1H-4-substituted imidazole compounds were synthesized and identified as potent and selective histamine (HA) H3 receptor ligands. These ligands establish that HA H3 antagonists exhibit stereoselective and conformational preferences in their binding to the HA H3 receptor. Structure-activity relationships were determined in vitro by HA H3 receptor-binding affinities using [3H]Nα-methylhistamine and rat cerebral cortical tissue homogenates. Several derivatives containing olefin, amide, and acetylene functional groups were identified as potent HA H3 receptor ligands. In the olefin series, GT-2227 (4-(6-cyclohexylhex-cis-3-enyl)imidazole) was identified as a potent HA H3 receptor ligand with aK i of 4.2 ± 0.6 nM, while thetrans isomer (GT-2228) displayed a reduced potency (K i = 15.2 ± 2.4 nM). GT-2227 was also found to have excellent central nervous system penetration in an ex vivo binding paradigm (ED50 = 0.7 mg/kg i.p.). In the acetylene series, GT-2260 and GT-2286 both exhibited high affinity (K i = 2.9 ± 0.2 and 0.95 ± 0.3 nM) and excellent central nervous system penetration profiles (ED50 = 0.43 and 0.48 mg/kg i.p., respectively). As a prototype for the series, GT-2227 showed high affinity for the human HA H3 receptor (3.2 nM) and minimal affinity for the human HA H1 (K i = 13,407 ± 540 nM) and H2 (K i = 4,469 ± 564 nM) receptor subtypes. GT-2227 also showed good selectivity for the HA H3 receptor over a broad spectrum of other neurotransmitter receptors (IC50 ≥ 1 μM). Furthermore, GT-2227 improved acquisition in a cognitive paradigm without behavioral excitation or effect on spontaneous locomotor activity. In summary, the present studies demonstrate the development of novel HA H3-selective ligands, and lend support for the use of such agents in the treatment of disorders associated with cognitive or attentional deficits. The American Society for Pharmacology and Experimental Therapeutics