Nicotinic Receptors and the Treatment of Attentional and Cognitive Deficits in Neuropsychiatric Disorders: Focus on the a7 Nicotinic Acetylcho-line Receptor as a Promising Drug Target for Schizophrenia

摘要

A large body of evidence shows that alpha7 nicotinic acetylcholine receptor (nAChR) is an important mechanism underlying attentional and cognitive deficits in schizophrenia. Several compounds acting as activators of alpha 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 alpha7 activators. Two classes of compounds are described, partial/full alpha7 agonists and alpha7 positive allosteric modulators (PAMs). Their critical pharmacological features are analysed by focussing on type of activity/selectivity at a7 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 alpha agonists. Such as limitations have not been seen for alpha7 PAMs, so that this class may offer a potential back-up strategy for alpha activators development. The empirical profiles proposed here might give pragmatical indications for the development and the optimization of a7 activators. Few issues need to be further optimized, i), in the clinic, mostly PK profiling, and, ii), at a preclinical level, downstream alpha receptors mechanisms involved in cognitive deficits. A successfully translation of alpha activators research for the treatment of schizophrenic patients will rely on a continuous clinical/preclinical cross-talk approach.