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.