The selective nicotinic acetylcholine receptor α7 agonist JN403 is active in animal models of cognition, sensory gating, epilepsy and pain

An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7

“…The hyperconnectivity observed in our study in 15q13.3 mice might also result from this imbalance of inhibition-excitation processes. In line with this hypothesis, it has been demonstrated that the activation of nAChA7Rs has an antiepileptic effect via increasing presynaptic GABAergic neurotransmission (Feuerbach et al, 2009). Interestingly, mice with reduced Chrna7 expression have less GABAA receptors in the hippocampus, as well as reduced expression of hippocampal GAD65 (GABA synthetic enzyme) (Adams et al, 2012).…”

“…Post-synaptic nAChA7Rs have been found on inhibitory GABAergic interneurons where they facilitate neuronal functioning (Morales et al, 2008). A reduced number of nAChA7Rs might result in reduction of inhibition and a consequent increase in excitability could lead to the deficient sensory and overall inhibition and epilepsy (Stevens et al, 2015) and to cognitive and learning disturbances observed in schizophrenia (Feuerbach et al, 2009). …”

The Antinociceptive Effects of Nicotinic Receptors α7-Positive Allosteric Modulators in Murine Acute and Tonic Pain Models

“…The homomeric a7 subunit is one subtype that is expressed abundantly in the central nervous system and in the periphery (Girod et al, 1999). nAChR a7 subtypes are characterized by their high calcium permeability and their rapid desensitization during agonist stimulation (Feuerbach et al, 2009) compared with other nAChR subtypes. In recent years, the a7 nAChR agonists were proposed as possible targets for cognitive enhancement, antinociception, and anti-inflammation properties (Damaj et al, 2000;Wang et al, 2005;de Jonge and Ulloa, 2007;Rowley et al, 2010;Thomsen et al, 2010).…”

“…These receptors are also present on immune and nonimmune cytokine-producing cells, including macrophages and keratinocytes (Wang and Wang, 2003;Pavlov and Tracey, 2004). Furthermore, a7 nAChR agonists, such as choline, CDP-choline, compound B, JN403 [(S)-(1-azabicyclo [2.2.2]oct-3-yl)-carbamic acid (S)-1-(2-fluoro-phenyl)-ethyl ester], and (2)-spiro[1-azabicyclo[2.2.2]octane-3,59-oxazolidin]-29-one (AR-R17779, exhibited anti-inflammatory effects in various inflammation and pain models in rodents (Damaj et al, 2000;Medhurst et al, 2008;Feuerbach et al, 2009;Gurun et al, 2009;van Maanen et al, 2009;Rowley et al, 2010;Marrero et al, 2011;Munro et al, 2012). Although a7 nAChR agonists showed beneficial effects in inflammatory animal models in some studies, these effects were not seen consistently in other studies (Gao et al, 2010).…”

Neuroimaging - Clinical Applications

“…The large number of studies on receptor structure and pharmacology makes α7 nAChR an extensively investigated receptor protein and the continued development of orthosteric ligands and allosteric modulators by the pharmaceutical industry testifies the importance of efforts to assess α7 nAChR expression and functionality in the living human brain (Bunnelle et al, 2004;Mazurov et al, 2006). Evidence of a correlation between α7 nAChR properties and brain performance has been provided by studies on the attentional and cognitive enhancement obtained by α7 nAChR agonists (Feuerbach et al, 2009;Levin et al, 1999;Roncarati et al, 2009) and positive allosteric modulators (Faghih et al, 2008;Timmermann et al, 2007) as well as on α7 nAChR related pharmacotherapeutic approaches for schizophrenia Olincy et al, 2006;Tregellas et al, 2011), anddementia (Bacher et al, 2010;Kitagawa et al, 2003;Thomsen et al, 2010). Furthermore, electrophysiological Ng et al, 2007) and behavioural data (Bitner et al, 2010;Pacini et al, 2010;Tietje et al, 2008) highlight the potential of α7 nAChR as therapeutic target for neurodegenerative diseases.…”