Identification and Pharmacological Characterization of a Series of New 1H-4-Substituted-Imidazoyl Histamine H3 Receptor Ligands

A new series of 1 H -4-substituted imidazole compounds were synthesized and identified as potent and selective histamine (HA) H 3 receptor ligands. These ligands establish that HA H 3 antagonists exhibit stereoselective and conformational preferences in their binding to the HA H 3 receptor. Structure-activity relationships were determined in vitro by HA H 3 receptor-binding affinities using [ 3 H]N α -methylhistamine and rat cerebral cortical tissue homogenates. Several derivatives containing olefin, amide, and acetylene functional groups were identified as potent HA H 3 receptor ligands. In the olefin series, GT-2227 (4-(6-cyclohexylhex- cis -3-enyl)imidazole) was identified as a potent HA H 3 receptor ligand with a K i of 4.2 ± 0.6 nM, while the trans 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 (ED 50 = 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 (ED 50 = 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 H 3 receptor (3.2 nM) and minimal affinity for the human HA H 1 ( K i = 13,407 ± 540 nM) and H 2 ( K i = 4,469 ± 564 nM) receptor subtypes. GT-2227 also showed good selectivity for the HA H 3 receptor over a broad spectrum of other neurotransmitter receptors (IC 50 ≥ 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 H 3- selective ligands, and lend support for the use of such agents in the treatment of disorders associated with cognitive or attentional deficits.