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  • The difficulty of characterizing nAChRs in the central nervo

    2022-11-18

    The difficulty of characterizing nAChRs in the central nervous system is also exemplified by early observations that nicotine caused no detectable effect when applied on a brain slice and it is only with the focal and high time resolution of more recent experiments that the effects of nicotinic neurotransmission became evident such as recently revealed for the human cortex [29]. Similarly, while it was observed that nicotine exposure, such as that associated with smoking, causes multiple physiological effects, it is only more recently that effects of nAChRs on the immune response became recognized [30].
    nAChR ligands – desirable properties Whereas the minimal requirements described above represent a sound basis of any drug discovery pathway, it is interesting to note that they were not necessarily followed carefully in even the most recent clinical trials. For example, it is documented that nAChRs resemble serotoninergic 5HT3 receptors both structurally and functionally, they share chaperones (RIC3) and, consequently, the cross reactivity between these two families of receptors might affect the general outcomes of nAChR ligand administration [31], [32]. In fact, it is this very point and the 5HT3 inhibition associated with EVP-6124 that some have argued brought to a halt to the development of this promising nAChR ligand for the treatment of AD based on gastrointestinal side effects [5]. Here it should be noted, however, that it is not clear that 5HT3 inhibition is necessarily an effect that should be avoided. The setron class of compounds (e.g., ondansetron) have been used clinically for decades to treat nausea associated with chemotherapy without major limiting side effects. Moreover, there has been an interest in 5HT3 receptor antagonists as putative cognitive enhancers for many years given their ability to increase TH588 release in the brain [33], [34] and to enhance cognitive function across multiple tasks in young and aged rats and non-human primates [1]. While ondansetron was found to be inactive in an AD clinical trial, [35], there are a number of additional setrons with promising effects in animal models that have not been rigorously evaluated in clinical trials including compounds that have potent effects at α7 nAChRs. An example is tropisetron, which has been shown in a variety of animal models relevant to both schizophrenia and AD to have cognitive-enhancing actions. Moreover, some relatively small clinical studies indicate that tropisetron can ameliorate cognitive impairments and negative symptoms in patients with schizophrenia [36], [37]. As EVP-6124 targeted the homomeric α7 nAChR, structural comparisons to the 5HT3 receptor can bring insight regarding receptor cross interactions. Alignment of the protein sequences encoding for the human α7 and 5HT3 receptors might provide initial information regarding the conserved regions and homologies. A single receptor results from the assembly of five subunits around an axis of pseudosymmetry formed by the ionic pore and while α7 receptors are composed by the arrangement of five identical subunits, the 5HT3 can be either homomeric composed by the 5HT3A subunit or heteromeric containing the 5HT3A and 5HT3B subunit or possibly 5HT3C, 5HT3D or 5HT3E. Database search reveals, however, an unexpected complexity and that the genes encoding for α7 presents two isoforms for CHNRA7 (α7) whereas three isoforms were reported for the sole 5HT3A gene (5HT3A). In addition, numerous variants were already identified for each gene, as reported in the sequencing of 64,000 human coding sequences (http://exac.broadinstitute.org, or http://gnomad.broadinstitute.org). This exome data set counts no less than 50 missense or loss of function mutations for CHRNA7. As a single amino acid difference can be found to have profound functional effects, these data indicate that given our current knowledge it is not yet possible to translate the large body of information collected from the human genome into the pharmacological properties of the receptors. Moreover, a further complexity of CHRNA7 genetic association arises from the partial duplication of exons 6–10 downstream on the same chromosome [38]. The identification of CHRFAM7A revealed a further difficulty in the interpretation of genomic sequences data. The analysis of the promotor sequence which regulates the expression of α7 revealed, however, a positive correlation between variant rs28531779 and schizophrenia but no association with the P50 auditory evoked potential [39]. These findings differ from a previous study [40] in which a correlation was observed between promoter variants with schizophrenia and associated P50 deficits. In spite of the multiple difficulties, genetic analysis and, more specifically, characterization of copy number provided novel and determinant correlations between α7 and cognitive deficits [41]. Specifically, it was observed that the location of chromosome 15 (15q13) is highly variable and is thought to be a hotspot for microdeletions associated with intellectual disabilities [42], [43], [44]. Individuals presenting either an increase in copy numbers or deletion in the 15q13 region and at the extreme, full deletion of the CHRNA7 gene, display marked intellectual disabilities, which further reinforces the relevance of cholinergic regulation in brain function. A more thorough analysis and description of the genetic analysis and correlation with brain function would go beyond the scope of this work.