Procognitive and neuroprotective activity of a novel alpha7 nicotinic acetylcholine receptor agonist for treatment of neurodegenerative and cognitive disorders

ABSTRACT The ␣7 nicotinic acetylcholine receptor (nAChR) is a promising target for treatment of cognitive dysfunction associated with Alzheimer's disease and schizophrenia. Here, we report the pharmacological properties of 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide [SEN12333 (WAY-317538)], a novel selective agonist of ␣7 nAChR. SEN12333 shows high affinity for the rat ␣7 receptor expressed in GH4C1 cells (K i ϭ 260 nM) and acts as full agonist in functional Ca 2ϩ flux studies (EC 50 ϭ 1.6 M). In whole-cell patch-clamp recordings, SEN12333 activated peak currents and maximal total charges similar to acetylcholine (EC 50 ϭ 12 M). The compound did not show agonist activity at other nicotinic receptors tested and acted as a weak antagonist at ␣3-containing receptors. SEN12333 treatment (3 mg/kg i.p.) improved episodic memory in a novel object recognition task in rats in conditions of spontaneous forgetting as well as cognitive disruptions induced via glutamatergic [5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); MK-801] or cholinergic (scopolamine) mechanisms. This improvement was blocked by the ␣7-selective antagonist methyllycaconitine, indicating that it is mediated by ␣7 activation. SEN12333 also prevented a scopolamine-induced deficit in a passive avoidance task. In models targeting other cognitive domains, including attention and perceptual processing, SEN12333 normalized the apomorphine-induced deficit of prepulse inhibition. Neuroprotection of SEN12333 was demonstrated in quisqualate-lesioned animals in which treatment with SEN12333 (3 mg/kg/day i.p.) resulted in a significant protection of choline acetyltransferase-positive neurons in the lesioned hemisphere. Cumulatively, our results demonstrate that the novel ␣7 nAChR agonist SEN12333 has procognitive and neuroprotective properties, further demonstrating utility of ␣7 agonists for treatment of neurodegenerative and cognitive disorders. The family of nicotinic acetylcholine receptors, which comprises 16 different subunits in human (␣1-7, ␣9 -10, ␤1-4, ␦, ε, and ␥) that can form many functional homo-and heteropentameric receptor ion channel combinations, contributes to cholinergic neurotransmission in the nervous system and at the neuromuscular junction. The ␣7 nicotinic acetylcholine receptors (nAChRs) are rapidly desensitizing ligand-gated ion channels that are abundantly expressed in the cerebral cortex and the hippocampus, a limbic structure intimately linked to attention processing and memory formatio