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NEUROPHARMACOLOGY

Procognitive and Neuroprotective Activity of a Novel 7 Nicotinic Acetylcholine Receptor Agonist for Treatment of Neurodegenerative and Cognitive Disorders

Siena Biotech S.p.A., Siena, Italy (R.R., C.S., H.B., M.G., U.Z., C.G., G.C.T.); and Discovery Neuroscience Wyeth Research, Princeton, New Jersey (T.A.C., S.M.G., S.A., B.J., D.K., C.K., S.H., J.D.)

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 = 260 nM) and acts as full agonist in functional Ca²⁺ flux studies (EC₅₀ = 1.6 µM). In whole-cell patch-clamp recordings, SEN12333 activated peak currents and maximal total charges similar to acetylcholine (EC₅₀ = 12 µM). 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.

Address correspondence to: Dr. Renza Roncarati, Strada del Petriccio e Belriguardo, 35, 53100 Siena, Italy. E-mail: rroncarati{at}sienabiotech.it