title: Characterization of RO5126946, a Novel α7 nicotinic acetylcholine receptor-positive allosteric modulator.
abstract: Both preclinical evidence and clinical evidence suggest that α7 nicotinic acetylcholine receptor activation (α7nAChR) improves cognitive function, the decline of which is associated with conditions such as Alzheimer's disease and schizophrenia. Moreover, allosteric modulation of α7nAChR is an emerging therapeutic strategy in an attempt to avoid the rapid desensitization properties associated with the α7nAChR after orthosteric activation. We used a calcium assay to screen for positive allosteric modulators (PAMs) of α7nAChR and report on the pharmacologic characterization of the novel compound RO5126946 (5-chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide), which allosterically modulates α7nAChR activity. RO5126946 increased acetylcholine-evoked peak current and delayed current decay but did not affect the recovery of α7nAChRs from desensitization. In addition, RO5126946's effects were absent when nicotine-evoked currents were completely blocked by coapplication of the α7nAChR-selective antagonist methyl-lycaconitine. RO5126946 enhanced α7nAChR synaptic transmission and positively modulated GABAergic responses. The absence of RO5126946 effects at human α4β2nAChR and 5-hydroxytryptamine 3 receptors, among others, indicated selectivity for α7nAChRs. In vivo, RO5126946 is orally bioavailable and brain-penetrant and improves associative learning in a scopolamine-induced deficit model of fear conditioning in rats. In addition, procognitive effects of RO5126946 were investigated in the presence of nicotine to address potential pharmacologic interactions on behavior. RO5126946 potentiated nicotine's effects on fear memory when both compounds were administered at subthreshold doses and did not interfere with procognitive effects observed when both compounds were administered at effective doses. Overall, RO5126946 is a novel α7nAChR PAM with cognitive-enhancing properties.
authors.affiliation: Roche Palo Alto, Palo Alto, California (S.S., T.W., R.H., H.M., K.B., M.E.M., D.C.B.); F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Discovery Neuroscience, Grenzacherstrasse, Basel, Switzerland (F.K., L.S.); gRED South San Francisco, California (D.M.); HiQScreen Sarl, Geneva, Switzerland (D.B.); and Psychogenics Inc., Tarrytown, New York (G.C.T.).
authors.forename: Sunil
authors.initials: S
authors.lastname: Sahdeo
authors.affiliation: Roche Palo Alto, Palo Alto, California (S.S., T.W., R.H., H.M., K.B., M.E.M., D.C.B.); F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Discovery Neuroscience, Grenzacherstrasse, Basel, Switzerland (F.K., L.S.); gRED South San Francisco, California (D.M.); HiQScreen Sarl, Geneva, Switzerland (D.B.); and Psychogenics Inc., Tarrytown, New York (G.C.T.).
authors.forename: Tanya
authors.initials: T
authors.lastname: Wallace
authors.affiliation: Roche Palo Alto, Palo Alto, California (S.S., T.W., R.H., H.M., K.B., M.E.M., D.C.B.); F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Discovery Neuroscience, Grenzacherstrasse, Basel, Switzerland (F.K., L.S.); gRED South San Francisco, California (D.M.); HiQScreen Sarl, Geneva, Switzerland (D.B.); and Psychogenics Inc., Tarrytown, New York (G.C.T.).
authors.forename: Ryoko
authors.initials: R
authors.lastname: Hirakawa
authors.affiliation: Roche Palo Alto, Palo Alto, California (S.S., T.W., R.H., H.M., K.B., M.E.M., D.C.B.); F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Discovery Neuroscience, Grenzacherstrasse, Basel, Switzerland (F.K., L.S.); gRED South San Francisco, California (D.M.); HiQScreen Sarl, Geneva, Switzerland (D.B.); and Psychogenics Inc., Tarrytown, New York (G.C.T.).
authors.forename: Frederic
authors.initials: F
authors.lastname: Knoflach
authors.affiliation: Roche Palo Alto, Palo Alto, California (S.S., T.W., R.H., H.M., K.B., M.E.M., D.C.B.); F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Discovery Neuroscience, Grenzacherstrasse, Basel, Switzerland (F.K., L.S.); gRED South San Francisco, California (D.M.); HiQScreen Sarl, Geneva, Switzerland (D.B.); and Psychogenics Inc., Tarrytown, New York (G.C.T.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertrand
authors.affiliation: Roche Palo Alto, Palo Alto, California (S.S., T.W., R.H., H.M., K.B., M.E.M., D.C.B.); F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Discovery Neuroscience, Grenzacherstrasse, Basel, Switzerland (F.K., L.S.); gRED South San Francisco, California (D.M.); HiQScreen Sarl, Geneva, Switzerland (D.B.); and Psychogenics Inc., Tarrytown, New York (G.C.T.).
authors.forename: Hans
authors.initials: H
authors.lastname: Maag
authors.affiliation: Roche Palo Alto, Palo Alto, California (S.S., T.W., R.H., H.M., K.B., M.E.M., D.C.B.); F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Discovery Neuroscience, Grenzacherstrasse, Basel, Switzerland (F.K., L.S.); gRED South San Francisco, California (D.M.); HiQScreen Sarl, Geneva, Switzerland (D.B.); and Psychogenics Inc., Tarrytown, New York (G.C.T.).
authors.forename: Dinah
authors.initials: D
authors.lastname: Misner
authors.affiliation: Roche Palo Alto, Palo Alto, California (S.S., T.W., R.H., H.M., K.B., M.E.M., D.C.B.); F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Discovery Neuroscience, Grenzacherstrasse, Basel, Switzerland (F.K., L.S.); gRED South San Francisco, California (D.M.); HiQScreen Sarl, Geneva, Switzerland (D.B.); and Psychogenics Inc., Tarrytown, New York (G.C.T.).
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Tombaugh
authors.affiliation: Roche Palo Alto, Palo Alto, California (S.S., T.W., R.H., H.M., K.B., M.E.M., D.C.B.); F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Discovery Neuroscience, Grenzacherstrasse, Basel, Switzerland (F.K., L.S.); gRED South San Francisco, California (D.M.); HiQScreen Sarl, Geneva, Switzerland (D.B.); and Psychogenics Inc., Tarrytown, New York (G.C.T.).
authors.forename: Luca
authors.initials: L
authors.lastname: Santarelli
authors.affiliation: Roche Palo Alto, Palo Alto, California (S.S., T.W., R.H., H.M., K.B., M.E.M., D.C.B.); F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Discovery Neuroscience, Grenzacherstrasse, Basel, Switzerland (F.K., L.S.); gRED South San Francisco, California (D.M.); HiQScreen Sarl, Geneva, Switzerland (D.B.); and Psychogenics Inc., Tarrytown, New York (G.C.T.).
authors.forename: Ken
authors.initials: K
authors.lastname: Brameld
authors.affiliation: Roche Palo Alto, Palo Alto, California (S.S., T.W., R.H., H.M., K.B., M.E.M., D.C.B.); F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Discovery Neuroscience, Grenzacherstrasse, Basel, Switzerland (F.K., L.S.); gRED South San Francisco, California (D.M.); HiQScreen Sarl, Geneva, Switzerland (D.B.); and Psychogenics Inc., Tarrytown, New York (G.C.T.).
authors.forename: Marcos E
authors.initials: ME
authors.lastname: Milla
authors.affiliation: Roche Palo Alto, Palo Alto, California (S.S., T.W., R.H., H.M., K.B., M.E.M., D.C.B.); F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Discovery Neuroscience, Grenzacherstrasse, Basel, Switzerland (F.K., L.S.); gRED South San Francisco, California (D.M.); HiQScreen Sarl, Geneva, Switzerland (D.B.); and Psychogenics Inc., Tarrytown, New York (G.C.T.) dbutton@acorda.com.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Button
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002478:Cells, Cultured; D003071:Cognition / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology; D017470:Receptors, Glutamate / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000187:drug effects*
chemical_list: C000590932:5-chloro-N-(2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropyl)-2-methoxybenzamide; D001549:Benzamides; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate; D013449:Sulfonamides; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine