title: Procognitive and neuroprotective activity of a novel alpha7 nicotinic acetylcholine receptor agonist for treatment of neurodegenerative and cognitive disorders.
abstract: The alpha7 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 alpha7 nAChR. SEN12333 shows high affinity for the rat alpha7 receptor expressed in GH4C1 cells (K(i) = 260 nM) and acts as full agonist in functional Ca(2+) flux studies (EC(50) = 1.6 microM). In whole-cell patch-clamp recordings, SEN12333 activated peak currents and maximal total charges similar to acetylcholine (EC(50) = 12 microM). The compound did not show agonist activity at other nicotinic receptors tested and acted as a weak antagonist at alpha3-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 alpha7-selective antagonist methyllycaconitine, indicating that it is mediated by alpha7 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 alpha7 nAChR agonist SEN12333 has procognitive and neuroprotective properties, further demonstrating utility of alpha7 agonists for treatment of neurodegenerative and cognitive disorders.
authors.affiliation: Siena Biotech SpA, Siena, Italy. rroncarati@sienabiotech.it
authors.forename: Renza
authors.initials: R
authors.lastname: Roncarati
authors.forename: Carla
authors.initials: C
authors.lastname: Scali
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Comery
authors.forename: Steven M
authors.initials: SM
authors.lastname: Grauer
authors.forename: Suzan
authors.initials: S
authors.lastname: Aschmi
authors.forename: Hendrick
authors.initials: H
authors.lastname: Bothmann
authors.forename: Brian
authors.initials: B
authors.lastname: Jow
authors.forename: Dianne
authors.initials: D
authors.lastname: Kowal
authors.forename: Marco
authors.initials: M
authors.lastname: Gianfriddo
authors.forename: Cody
authors.initials: C
authors.lastname: Kelley
authors.forename: Ugo
authors.initials: U
authors.lastname: Zanelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Ghiron
authors.forename: Simon
authors.initials: S
authors.lastname: Haydar
authors.forename: John
authors.initials: J
authors.lastname: Dunlop
authors.forename: Georg C
authors.initials: GC
authors.lastname: Terstappen
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018722:Nicotinic Agonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011869:Radioligand Assay; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C540749:5-morpholin-4-ylpentanoic acid (4-pyridin-3-ylphenyl)amide; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D009025:Morpholines; D018696:Neuroprotective Agents; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D002118:Calcium