P4‐196: Assessment of PF‐04995274 in scopolamine‐disrupted Morris water maze compared to and in combination with donepezil

Serotonin 5-HT4 agonism has been proposed as a cognitive enhancing mechanism. It has been shown to enhance release of acetylcholine in frontal cortex and hippocampus and to reverse the cognitive deficits induced by treatment with anticholinergic drugs in non-clinical behavioral models. The loss of cholinergic function believed to be a major cause of the cognitive decline seen in Alzheimer's disease. In addition, compounds that have been shown to increase acetylcholine function, such as the acetylcholinesterase inhibitor donepezil, have demonstrated efficacy in the treatment of cognitive deficits in AD patients while compounds that block ACh activity, such as scopolamine, have been shown to disrupt learning and memory. A 5-HT4 partial agonist, PF-04995274, was tested in a scopolamine disrupted Morris water maze rat model to assess its cognitive enhancing properties. In these experiments it was compared directly to and tested in combination with donepezil. Compounds were administered once daily for 4 days, prior to testing. Rats treated with the 5-HT4 compound showed improved acquisition of the Morris water maze task. Performance was equivalent to the maximum acquisition seen in rats dosed with donepezil alone in the same task. When combined with a sub-active dose of donepezil, a trend suggestive an additive effect on cognitive enhancement was observed. Exposures of PF-4995274 obtained in brain, plasma and CSF were suggestive of ∼40% receptor occupancy of 5-HT4 partial agonist. These findings support the potential use of 5-HT4 agonists in treating Alzheimer's disease-related cognitive deficits. Furthermore, the results of combining the compound with a subactive dose of donepezil demonstrates the therapeutic potential of our current 5-HT4 partial agonist as an add-on therapy without any PK or PD related DDIs. A trend towards an additive effect suggests that combination treatment might yield improved results and/or allow reduction of donepezil dose.