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    • Altogether the situations described above clearly impede the

    2023-03-17

    Altogether, the situations described above clearly impede the critical steps of drug discovery and development and the scientific process in general [14]. In conclusion, it is the opinion of these authors that many exciting lines of drug discovery (which includes those devoted to nAChR ligands) have been prematurely discontinued and labeled as “treatment failures” based on a variety of confounding factors that may not be related to the true potential of a Nicotine as a pro-cognitive agent. Crossing the mirror, such as in the classic novel “Alice in Wonderland”, brought, a variety of additional surprises. First, the hypothesis that a specific compound displaying a high affinity for a given receptor subtype would affect only this class of receptors and that the presence of an agonist would activate in a sustained manner the selected target was confronted with the complex nature of the biological response. The development of highly selective treatment modalities focused on very specific pathophysiologic targets for the treatment of neuropsychiatric disorders is a reductionist approach that has dominated the of field drug discovery for decades. However, this strategy has not been widely successful [15], [4], and this may be due (at least in part) to our poor understanding of the pathophysiology of these disorders. A quick perusal of the literature reveals that most widely prescribed (FDA-approved) drugs for neurologic and psychiatric disorders (i.e., drugs that have stood the test for efficacy in clinical trials such as anticonvulsants, antidepressants, antipsychotics) affect multiple receptors and other targets across different neuronal phenotypes [16], [17], [18]. In the case of current therapy for Alzheimer’s disease (AD), even the commonly prescribed drug donepezil, which is classified as a selective acetylcholinesterase inhibitor, is also a potent agonist at sigma-1 receptors at therapeutically relevant concentrations [19], [20]. Moreover, the n-methyl-d-aspartate (NMDA) antagonist and AD treatment, memantine, also blocks serotonin 5-HT3 and nicotinic α4β2 nAChRs at therapeutically relevant concentrations [21], [22].
    nAChRs as therapeutic targets The first and probably most relevant question to tackle here is “Does the nAChRs constitute the ideal target” as initially thought? Whereas historical findings revealed that nAChRs are determinant for signal transmission at the neuromuscular junction, their contribution in the nervous system was more obscure [23], [24]. In the context of nAChR selectivity and the treatment of cognitive disorders, the field has concentrated primarily on developing ligands selective for heteromeric α4β2 and homomeric α7 nAChRs. This is because these receptor subtypes are thought to be the most prevalent in the mammalian brain particularly in memory-related areas such as the hippocampus and cerebral cortex and since other subtypes (e.g., α3β4 nAChRs) have been associated with undesired side effects (e.g., addiction) [25], [26]. However, complexity of the distribution of these nAChRs in the central nervous system (CNS), leads one to wonder whether subtype selectivity should be such a major consideration. Moreover, until the discovery of their broad pattern of expression in many organs or at the single cell level, investigations were limited by both the lack of appropriate histological tools [27] let alone functional assays. For the evaluation of the contributions of different nAChR subtypes in the CNS to cognitive processes, one has to go no further than the hippocampus to encounter the complexity. As reviewed by Rogers, 2009 [28], differing combinations of α7, α4β2, and α3β4 nAChRs found at strategic locations on interneurons in the hippocampus affect both inhibitory and excitatory tone to collectively drive theta wave synchronization and long-term potentiation. Given the additional physical properties of these receptor subtypes (i.e., different rates of activation and desensitization and variable permeability to calcium versus sodium), it is certainly not clear if pure selectivity at one of these nAChR subtypes is the most rational approach to drug development for cognitive disorders. Moreover, while traditional ligand-binding methods, immunohistochemistry, and to some extent in vivo imaging, have provided some knowledge of how nAChR subtypes in the hippocampus are affected by age and dementia, they may be inadequate for determining the finer details of nAChR involvement in local circuitry [28].