Ponesimod An alternative to the agonist or antagonist potent
An alternative to the agonist or antagonist potential in drug discovery is the positive allosteric modulator (PAM) approach, which can augment the normal processes of neurotransmission as opposed to directly replacing or antagonizing them. PAMs are thought to bind to sites that are distinct from the well-conserved (orthosteric) agonist binding domains. This approach has been very successful for the therapeutic development of sedative and anxiolytic benzodiazepines, which are PAMs of GABAA receptors, which belong to the same superfamily of ligand-gated ion channels as nAChRs . In the nAChR field most of the attention on PAMs has been focused on the α7 nAChR thus far with compounds divided into two classes based on their functional properties: type I (e.g., NS-1738 , or CCMI ) and type II (e.g., PNU-120596 ). Type I PAMs, defined as molecules that predominately affect the apparent peak current, agonist sensitivity, and Hill coefficient, but not the receptor desensitization profile, and Type II PAMs, compounds that possess the aforementioned properties described for Type I PAMs, as well as the ability to modify the desensitization profile of agonist responses . It has been argued that type II PAMs are less prone to induce tolerance, which may occur after the chronic administration of nAChR agonists, whereas, type I PAMs, may have advantages over type II PAMs since they can minimize potential calcium induced cytotoxicity , . Preclinical studies indicate that α7 nAChR PAMs can enhance cognition in aging and AD-related animal models  as well as improve cognitive impairments and positive and negative signs in schizophrenia-related animal models . To date, the nAChR PAM approach to the therapeutics of neuropsychiatric disorders has not been rigorously pursued. Interestingly, the type 1 PAM, AVL-3288 was recently found in a small phase 1 clinical study to be safe in normal human (nonsmoking) volunteers and to exert positive (albeit non-statistically significant) effects on neurocognition .
Nicotinic ligands and smoking cessation Development of a synthetic partial agonist active at the major Ponesimod α4β2 nAChRs yielded the compound varenicline that was introduced under the name Chantix and remains, nowadays, one of the best methods for smoking cessation . Whereas clinical studies have focused mainly on the α4β2 nAChRs and use of partial agonists, new alternatives targeting the α3β4 receptors have also emerged . Interestingly, and in agreement with previous elements presented herein, compounds targeting the α3β4 presented no cardiovascular issues in animal models but might open new possibilities to address receptors that are highly expressed in midbrain brain pathways including the interpeduncular nucleus and the fasciculus retroflexus , a pathway that modulates basal negative emotional responses and has been suggested to be implicated in neuroadaptations .
Conclusions and future directions Interest in nicotinic ligands as potential therapeutic agents (particularly for cognitive disorders) began nearly 30 years ago when it was first demonstrated that the tobacco alkaloid nicotine could improve cognitive function in nicotine-deprived smokers, as well as nonsmokers and experimental animals . Numerous animal and human studies now indicate that nicotine has the potential to improve multiple domains of cognition including sustained attention and distractibility, working memory, recognition memory, and executive function . While nicotine would not be considered as an antipsychotic drug, it has been shown to improve some psychiatric symptoms in schizophrenia (e.g., the negative symptoms) and to improve sensory gating and prepulse inhibition in animals and humans . It also has neuroprotective activity in multiple disease models (i.e., both in vitro and in vivo) , while other data suggest that nicotine might have potential as an antidepressant. Here, there is a relatively well-established connection between smoking and depression and, moreover, a significant number of nicotinic ligands (including nicotine) have shown efficacy in rodent models of antidepressant efficacy . Collectively, these data indicate a therapeutic potential for nicotine across a variety of neuropsychiatric and neurodegenerative illnesses including attention deficit hyperactivity disorder (ADHD), schizophrenia, major depression, Alzheimer’s disease, mild cognitive impairment (MCI), and Parkinson’s disease. Unfortunately, concerns about the short half-life, cardiovascular side effects, and abuse potential have limited enthusiasm for nicotine as a therapeutic agent to date. Here it is interesting to note, however, that despite the known sympathomimetic effects of nicotine (elevated heart rate and cardiac contractility, vasoconstriction, transient effects on blood pressure) , nicotine delivered via a transdermal patch for smoking cessation in smokers with cardiovascular disease showed no increased risk of cardiovascular events compared with placebo . Moreover, nicotine delivered via a transdermal patch to patients with MCI improved cognition without signs of significant side effects . In an attempt to alleviate the limitations related to nicotine administration, several companies have developed a wide range of nAChRs ligands aiming at a high degree of selectivity and high affinity for specific subtypes of receptors. While many compounds have shown efficacy across multiple preclinical models of neuropsychiatric disorders these compounds failed to develop into successful approved drugs. The recent failures of nAChR ligands in AD and schizophrenia clinical trials have reduced enthusiasm for this therapeutic strategy and many pharmaceutical companies have at least temporarily abandoned this field of research. Overviewing the reasons for the lack of translation from preclinical to clinical trials it is obvious that some of the discrepancies are associated with: a) differences between the model and the patient conditions, b) the concentration ranges that were tested, c) the need to show a superior efficacy of a given compound in supplement of an already existing treatment, etc. 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 compound as a pro-cognitive agent. The remarkable progress that has been made over the last three decades in our understanding of nAChRs as unique ligand-gated ion channels and their contributions to brain signaling and information processing are expected to bring new possibilities in the field of novel drug discovery.