P4-387: 5-HT 6 receptor antagonist SB-742457 as a novel cognitive enhancing agent for Alzheimer’s disease

Abstract

5–HT6 receptors are expressed in brain regions that are involved in learning and memory. Preclinical studies have demonstrated that 5–HT6 receptor antagonism can exert cognitive enhancing effects, in part by inducing increases in the extracellular levels of acetylcholine, glutamate, noradrenaline and dopamine in the frontal cortex. These properties suggest potential utility in treating the cognitive and behavioural problems characteristic of AD. The quinolinylpiperazine derivative SB–742457 is a highly selective 5–HT6 receptor antagonist with high affinity to the human receptor (pKi = 9.63), and is orally bioavailable with improved brain penetration in rats over previously developed compounds. The current study aimed to examine the cognitive enhancing potential of SB–742457. SB–742457 was tested in a series of preclinical cognition models and the potential underlying mechanisms examined. In a Novel Object Recognition paradigm, subchronic daily oral pre–dosing of SB–742457 (1.5 mg/kg) significantly reversed the impairment induced by the cholinergic antagonist scopolamine (0.5 mg/kg, 20 minutes prior to acquisition). Acute predosing at 0.5 – 4.5 mg/kg also reversed scopolamine (0.8 mg/kg)–induced amnesia in a passive avoidance paradigm. In the Morris water maze using aged rats with spatial task deficits, subchronic daily oral pre–dosing of SB–742457 (1.5 mg/kg) improved spatial learning performance, while task retention was improved by 0.5 and 1.5 mg/kg of the compound. Attempts to understand the underlying mechanisms show that acute oral administration of SB–742457 (1, 3, 10 mg/kg) induced significant increases in extracellular levels of glutamate and acetylcholine in the medial prefrontal cortex of freely moving rats. Interestingly, chronic administration of 1.5 mg/kg of SB–742457 also upregulated the expression of polysialylated–NCAM on hippocampal neurons, consistent with its ability to enhance cognition. AD remains a devastating condition with great unmet medical needs. SB–742457, through the induction of specific neurochemical and neural plastic changes in the brain, provides a clear mechanistic differentiation from donepezil and thus represents a novel agent with the potential to tackle the cognitive and behavioural dysfunctions associated with AD.