The ␣7 nicotinic acetylcholine receptor (nAChR) plays an important role in cognitive processes and may represent a drug target for treating cognitive deficits in neurodegenerative and psychiatric disorders. In the present study, we used a novel ␣7 nAChR-selective agonist, 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) to interrogate cognitive efficacy, as well as examine potential cellular mechanisms of cognition. Exhibiting high affinity to native rat (K i ϭ 10.8 nM) and human (K i ϭ 16.7 nM) ␣7 nAChRs, A-582941 enhanced cognitive performance in behavioral assays including the monkey delayed matching-to-sample, rat social recognition, and mouse inhibitory avoidance models that capture domains of working memory, short-term recognition memory, and long-term memory consolidation, respectively. In addition, A-582941 normalized sensory gating deficits induced by the ␣7 nAChR antagonist methyllycaconitine in rats, and in DBA/2 mice that exhibit a natural sensory gating deficit. Examination of signaling pathways known to be involved in cognitive function revealed that ␣7 nAChR agonism increased extracellular-signal regulated kinase 1/2 (ERK1/2) phosphorylation in PC12 cells. Furthermore, increases in ERK1/2 and cAMP response element-binding protein (CREB) phosphorylation were observed in mouse cingulate cortex and/or hippocampus after acute A-582941 administration producing plasma concentrations in the range of ␣7 binding affinities and behavioral efficacious doses. The MEK inhibitor SL327 completely blocked ␣7 agonist-evoked ERK1/2 phosphorylation. Our results demonstrate that ␣7 nAChR agonism can lead to broad-spectrum efficacy in animal models at doses that enhance ERK1/2 and CREB phosphorylation/activation and may represent a mechanism that offers potential to improve cognitive deficits associated with neurodegenerative and psychiatric diseases, such as Alzheimer's disease and schizophrenia.

Background and purpose: Selective cannabinoid CB 2 receptor agonists have demonstrated analgesic activity across multiple preclinical pain models. AM1241 is an indole derivative that exhibits high affinity and selectivity for the CB 2 binding site and broad spectrum analgesic activity in rodent models, but is not an antagonist of CB 2 in vitro functional assays. Additionally, its analgesic effects are m-opioid receptor-dependent. Herein, we describe the in vitro and in vivo pharmacological properties of A-796260, a novel CB 2 agonist. Experimental approach: A-796260 was characterized in radioligand binding and in vitro functional assays at rat and human CB 1 and CB 2 receptors. The behavioural profile of A-796260 was assessed in models of inflammatory, post-operative, neuropathic, and osteoarthritic (OA) pain, as well as its effects on motor activity. The receptor specificity was confirmed using selective CB 1 , CB 2 and m-opioid receptor antagonists. Key results: A-796260 exhibited high affinity and agonist efficacy at human and rat CB 2 receptors, and was selective for the CB 2 vs CB 1 subtype. Efficacy in models of inflammatory, post-operative, neuropathic and OA pain was demonstrated, and these activities were selectively blocked by CB 2 , but not CB 1 or m-opioid receptor-selective antagonists. Efficacy was achieved at doses that had no significant effects on motor activity. Conclusions and implications: These results further confirm the therapeutic potential of CB 2 receptor-selective agonists for the treatment of pain. In addition, they demonstrate that A-796260 may be a useful new pharmacological compound for further studying CB 2 receptor pharmacology and for evaluating its role in the modulation of pain.

Background and purpose: The CB 2 receptor has been proposed as a novel target for the treatment of pain, and CB 2 receptor agonists defined in in vitro assays have demonstrated analgesic activity in animal models. Based on its in vivo analgesic efficacy, AM1241 has been classified as a CB 2 -selective agonist. However, in vitro characterization of AM1241 in functional assays has not been reported. Experimental approach: In this study, AM1241 was characterized across multiple in vitro assays employing heterologous recombinant receptor expression systems to assess its binding potencies at the human CB 2 and CB 1 receptors and its functional efficacies at the human CB 2 receptor. Key results: AM1241 exhibited distinct functional properties depending on the assay conditions employed, a unique profile in contrast to those of the agonist CP 55,940 and the inverse agonist SR144528. AM1241 displayed neutral antagonist activities in FLIPR and cyclase assays. However, when cyclase assays were performed using lower forskolin concentrations for stimulation, AM1241 exhibited partial agonist efficacy. In addition, it behaved as a partial agonist in ERK (or MAP) kinase assays. Conclusions and implications:The unusual phenomenon of inconsistent functional efficacies suggests that AM1241 is a protean agonist at the CB 2 receptor. We postulate that functional efficacies displayed by protean agonists in various assay systems may depend on the levels of receptor constitutive activities exhibited in the assay systems, and therefore, efficacies observed in in vitro assays may not predict in vivo activities.

The potential ecotoxicity of nanosized zinc oxide (ZnO), synthesized by the polyol process, was investigated using common Anabaena flos-aquae cyanobacteria and Euglena gracilis euglenoid microalgae. The photosynthetic activities of these microorganisms, after addition of ZnO nanoparticles, varied with the presence of protective agents such as tri-n-octylphosphine oxide (TOPO) and polyoxyethylene stearyl ether (Brij-76) used to control particle size and shape during the synthesis. In the case of Anabaena flos-aquae , the photosynthetic activity, after addition of ZnO, ZnO-TOPO, and ZnO-Brij-76, decreased progressively due to stress induced by the presence of the nanoparticles in the culture medium. After contact with ZnO-TOPO nanoparticles, this decrease was followed by cell death. On the other hand, after 10 days, a progressive increase of the photosynthetic activity was observed after contact with ZnO and ZnO-Brij-76 nanoparticles. In the case of Euglena gracilis , cell death was observed after contact with all nanoparticles. Transmission electron microscopy (TEM) analyses of ultrathin sections of microorganisms showed that polysaccharides produced by Anabaena flos-aquae avoid particle internalization after contact with ZnO and ZnO-Brij-76 nanoparticles. On the other hand, nanoparticle internalization was observed after contact with all nanoparticles in the presence of Euglena gracilis and also with ZnO-TOPO nanoparticles after contact with Anabaena flos-aquae .