O3-05-02: Peptidomimetics derived from the amyloid precursor protein (APP) as potential therapeutic agents in Alzheimer’s disease

Abstract

of several neurotransmitters in the brain and enhance cognition in rodent models. Several H3 antagonists are being developed as symptomatic agents for the treatment of cognitive deficits in Alzheimer’s Disease and other dementias. Objective: To investigate the in vitro and in vivo properties of GSK189254, a novel non-imidazole histamine H3 receptor antagonist. Methods: GSK189254 was profiled in standard in vitro binding and functional assays. In vivo oral activity of GSK189254 was assessed in several assays including ex vivo binding, cognition models and EEG. Results: GSK189254 had high affinity for native H3 receptors expressed in human and rat cerebral cortex (pKi 9.59 and 8.58 respectively) and for human and rat recombinant H3 receptors (pKi 9.90 and 9.17 respectively). GSK189254 was highly selective for H3 receptors ( 10000-fold vs other receptors, ion channels and transporters) and exhibited high functional antagonist potency at the human recombinant H3 receptor in vitro (pA2 9.1 vs imetit-induced inhibition of forskolin-stimulated cAMP accumulation). In vitro autoradiography studies with [3H]-GSK189254 in rat brain slices demonstrated a specific binding pattern consistent with H3 receptor distribution in cortex, hippocampus, striatum and hypothalamus. Specific [3H]-GSK189254 labelling was also observed in post-mortem cortex and hippocampus from human control and Alzheimer’s disease brains. Following oral administration in rats, GSK189254 exhibited high H3 receptor occupancy in the cerebral cortex (ED50 0.17mg/kg from ex vivo binding studies) indicative of good brain penetration, and potently reversed drinking induced by the H3 selective agonist (R)-alpha-methylhistamine (ID50 0.05mg/kg), supporting functional blockade of H3 receptors in vivo. GSK189254 (0.1-3mg/kg) exhibited efficacy in a number of rodent models of cognitive function including object recognition (48h delay), passive avoidance (scopolamine-induced amnesia) and water maze (aged animals). In addition, GSK189254 induced a transient increase in wakefulness in the rat during the light phase, and a corresponding decrease in slow wave sleep 2. Conclusion: Given these effects on cognition and alertness in preclinical species, the H3 antagonist GSK189254 has the potential to be a new therapeutic agent for the symptomatic treatment of Alzheimer’s Disease and other dementias.