Improved treatment for Alzheimer's disease is a significant unmet medical need which is becoming even more critical given the rise in the number of patients and the substantial economic burden. The current standards of care, acetylcholinesterase inhibitors (AChEIs), are hindered by GI side effects due to their nonselective activation of muscarinic and nicotinic receptors. Recently, the highly selective M1 positive allosteric modulator PQCA has been demonstrated to improve cognition in a variety of rodent and non-human primate cognition models without producing significant GI side effects. Here we describe the effect of PQCA and the AChEI donepezil on two clinically relevant and highly translatable touchscreen cognition tasks in NHPs, paired-associates learning (PAL) and the continuous performance task (CPT). Blockade of muscarinic signaling by scopolamine produced significant impairments in both PAL and CPT. PQCA and donepezil attenuated the scopolamine deficits in both tasks, and the action of these two compounds was similar in magnitude. In addition, the combination of sub-effective doses of PQCA and donepezil enhanced PAL performance. These results further suggest that M1 positive allosteric modulators have potential to reduce the cognitive deficits associated with Alzheimer's disease either as monotherapy or as an add-on to current standards of care.
- The American Society for Pharmacology and Experimental Therapeutics