Nicotinic Receptors and the Treatment of Attentional and Cognitive Deficits in Neuropsychiatric Disorders: Focus on the α7 Nicotinic Acetylcholine Receptor as a Promising Drug Target for Schizophrenia

Abstract

A large body of evidence shows that 7 nicotinic acetylcholine receptor (nAChR) is an important mechanism underlying attentional and cognitive deficits in schizophrenia. Several compounds acting as activators of 7 nAChRs have been identified and investigated for a potential therapeutic application. However, considering the complexity of neuropsychiatric disorders and the difficulty to meet an ideal product profile for drug discovery in the field, there is the need to define empirical product profiles from available data for the major 7 activators. Two classes of compounds are described, partial/full 7 agonists and 7 positive allosteric modulators (PAMs). Their critical pharmacological features are analysed by focussing on type of activity/selectivity at 7 nAChR, action in vivo in laboratory animal models, desired clinical activity, pharmacokinetics (PK)/dosing and safety/tolerability issues. Although the characterization of type of efficacy in vitro succeeded in the extrapolation to animal models and to patients, more efforts are needed to improve selectivity, PK/dosing and safety/tolerability features for 7 agonists. Such as limitations have not been seen for 7 PAMs, so that this class may offer a potential back-up strategy for 7 activators development. The empirical profiles proposed here might give pragmatical indications for the development and the optimization of 7 activators. Few issues need to be further optimized, i), in the clinic, mostly PK profiling, and, ii), at a preclinical level, downstream 7 receptors mechanisms involved in cognitive deficits. A successfully translation of 7 activators research for the treatment of schizophrenic patients will rely on a continuous clinical/preclinical cross-talk approach.

αConotoxin Arenatus IB[V11L,V16D] Is a Potent and Selective Antagonist at Rat and Human Native α7 Nicotinic Acetylcholine Receptors

“…α7 nAChRs are a therapeutic target for psychiatric and neurological disorders with cognitive or attentional impairments as well as other non-neurological conditions (Mazurov et al , 2006; Chiamulera and Fumagalli, 2007). Investigation of the physiological and pathological roles of α7 nAChRs requires selective ligands.…”

“…Consequently, α7 nAChRs are therapeutic targets for cognitive impairments in Alzheimer’s disease, schizophrenia and attention deficit hyperactivity disorder (Mazurov et al , 2006; Chiamulera and Fumagalli, 2007; Wilens and Decker, 2007). α7 nAChRs also have therapeutic potential in several other processes, including pain, inflammation and wound healing (Decker and Meyer, 1999; de Jonge and Ulloa, 2007).…”

Removing Obstacles in Neuroscience Drug Discovery: The Future Path for Animal Models

“…Given the level of dopamine receptor occupancy in these patients, an animal model of cognition that was responsive to D 2 dopamine receptor antagonists would need to be excluded from efforts to discover procognitive adjunctive treatments (Geyer, 2006a). By contrast, α7 nicotinic acetylcholine receptor activators (agonists and positive allosteric modulators) induce cognitive improvement in animal models of schizophrenia, although currently they do not appear to match the criteria for the “ideal” product profile (Chiamulera and Fumagalli, 2007). Based on positive effects in yet unvalidated animal models of cognition in terms of their relevance to schizophrenia, the α7 nicotinic acetylcholine partial agonist DMXBA has been evaluated in schizophrenia patients with preliminary positive results (Olincy et al ., 2006).…”

5-(5-(6-[11C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)-1H-indole as a potential PET radioligand for imaging cerebral α7-nAChR in mice

“…1–4 Because of the importance of α7-nAChR as potential drug target for treatment of various central disorders including schizophrenia, 5, 6 synthesis and pre-clinical examination of α7-nAChR subtype selective compounds receives substantial attention in industry and academia. 7–10 …”