Identification and pharmacological characterization of a series of new 1H-4-substituted-imidazoyl histamine H-3 receptor ligands

A new series of 1H-4-substituted imidazole compounds were synthesized and i dentified as potent and selective histamine (HA) H-3 receptor ligands. Thes e ligands establish that HA H-3 antagonists exhibit stereoselective and con formational 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 [H-3]N-alpha-methylhistamine and rat cerebral cortical tis sue homogenates. Several derivatives containing olefin, amide, and acetylen e functional groups were identified as potent HA H-3 receptor ligands. In t he olefin series, GT-2227 (4-(6-cyclohexylhex-cis-3-enyl)imidazole was iden tified as a potent HA H-3 receptor ligand with a K-i of 4.2 +/- 0.6 nM, whi le 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 pen etration in an ex vivo binding paradigm (ED50 = 0.7 mg/kg i.p.). In the ace tylene 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 penetrati on 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 H-3 receptor (3.2 nM) and minimal affinity for the human HA H-1 (K-i = 13,407 +/- 540 n M) 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 neu rotransmitter receptors (IC50 greater than or equal to 1 mu M). Furthermore , GT-2227 improved acquisition in a cognitive paradigm without behavioral e xcitation or effect on spontaneous locomotor activity. In summary, the pres ent 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 a ssociated with cognitive or attentional deficits.