Abstract

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]N^α-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 H_3-selective ligands, and lend support for the use of such agents in the treatment of disorders associated with cognitive or attentional deficits.