trials with ACh-esterase inhibitors. Interestingly, consistent with animal studies, AD patients also show dose-related decreases in anxiety and fear, suggesting that this agent may also have ► anxiolytic effects.
DMXB-A (3-(2,4-dimethoxy)benzylidene-anabaseine, GTS-21; Fig. 7) was the first a7 nAChR agonist to undergo clinical testing for AD. Initial studies in healthy volunteers indicated positive effects on reaction time, correct detection during digit vigilance, word and picture recognition, memory, immediate and delayed word recall, and performance speed in numeric and spatial working memory tasks. However, DMXB-A is a very weak agonist at a7 nAChRs, and potent antagonist at a4p2 nAChRs. These characteristics, combined with suboptimal pharmacoki-netic properties, have given rise to the search for new a7 nAChR agonists. Several pharmaceutical companies are advancing a7 nAChR partial and full agonists to clinical trials, e.g., TC-5619, SSR-180711, JN403 (Fig. 7), ABT-107, EVP-6124, AZD-0328, and R3487 (MEM3454; structures not disclosed). On the basis of publicly available information, the a7 nAChR partial agonist R3487 (MEM3454) appears to be currently ahead, with ongoing Phase 2a trials in AD and schizophrenia showing promising results. Significant progress has been made with the design of a7 nAChR allosteric modulators that are active in preclinical models, such as PNU-120596, NS-1738, A867744, (Fig. 7), and other compounds with undisclosed structures, and initial clinical evaluation is anticipated in the near future.
Schizophrenia Interest in specifically targeting a7 nAChRs to treat cognitive deficits in ► Schizophrenia was stimulated by evidence linking this receptor to deficits in auditory gating, a common ► Endophenotype associated with schizophrenia. Auditory gating is a form of sensory filtering whereby the amplitude of an auditory evoked potential is reduced if immediately preceded by a similar auditory tone ("prepulse"). Impairments in this filtering process are thought to lead to excessive sensory input, and result in poor performance in measures of attention. ► Single nucleotide polymorphisms (SNPs) in the gene encoding the a7 nAChR subunit (CHRNA7), and reduced levels of the encoded protein in patients with schizophrenia, further implicates a7 nAChR dysfunction as a contributing factor to this disease.
Although the clinical testing is still in the early phases, initial reports on the efficacy of a7 nAChR agonists for treating cognitive symptoms in schizophrenia are encouraging. For example, the a7 nAChR agonist DMXB-A (Fig. 7; see section Alzheimer's disease''), tested in a small ► double-blind study in patients with schizophrenia, normalized auditory gating and improved performance on a Neuropsychological Status (RBANS) scale and an attention subscale, with larger effect sizes than seen for nicotine or atypical antipsychotics in previous studies (Freedman et al. 2008). The effect of several doses of the a7 partial agonist MEM 3454 (also under investigation for cognitive improvement in AD; see section
Alzheimer's disease'') is currently being evaluated in a Phase 2 clinical study for cognitive impairment associated with schizophrenia. However, the development of some a7 nAChR agonists, e.g., PHA-568487 and PHA-543613 (Fig. 7), was halted in Phase 1 owing to safety concerns.
► Attention-deficit Hyperactivity Disorder Stimulant medications were introduced more than 60 years ago to treat the motor overactivity, impulsivity, and inattentive-ness associated with ADHD, and remain one of the main treatment options. Though highly effective against these core symptoms, stimulants often do not fully address the cognitive impairments associated with ADHD that are increasingly recognized as key factors in long-term outcomes, including academic and occupational success. Therefore, there is growing interest in developing nonstimulant medications with reduced abuse liability that can also address the cognitive aspects of ADHD. The development of nAChR ligands as potential treatments has been largely driven by the cognition-enhancing properties of nicotine and other nicotinic ligands (Wilens and Decker 2007). As with other cognitive disorders, ADHD patients use tobacco products at a higher rate than the general population, suggesting that nicotine may alleviate symptoms of ADHD. Indeed, when tested in clinical settings, nicotine has consistently demonstrated beneficial effects on disease symptom rating scales as well as on the measures of cognitive function. However, the ► Adverse Effect of nicotine, predominantly gastrointestinal and cardiovascular effects, preclude the broad use of nicotine to treat ADHD.
Three nicotinic compounds with selectivity for a4p2* nAChR subtypes have been evaluated in clinical efficacy and safety studies in ADHD patient populations. ABT-418 (Fig. 7) is a high-affinity ligand that displays full agonist activity at a4p2* nAChRs in vitro and specificity versus a3-containing ganglionic nAChRs. In a three-week study, transdermal ABT-418 was associated with a significantly higher proportion of subjects demonstrating moderately to significantly improved scores on the Clinical Global Impression scales versus placebo. ABT-418 was generally well tolerated with nicotine-like side effects (adverse effects), including dizziness and nausea.
A related nicotine analog ABT-089 (pozanicline; Fig. 7) also has high binding affinity and selectivity for the a4b2* receptor subtype, but very low efficacy at heterologously expressed a4P2* nAChRs. Interestingly, ABT-089 stimulates [3H]-DA release in brain slices and synaptosomal preparations with full efficacy when compared with nicotine. This difference between heterologous and native nAChR affinities suggests that ABT-089 may interact with additional nAChR subtypes, e.g., receptors containing a4, a6, b2, or P3 subunits (Yang et al. 2009). In a placebo-controlled clinical trial, ABT-089 significantly improved spatial ► working memory, attention, hyperactivity, and ► impulsivity on an adult ADHD Rating Scale, and was well tolerated with no observed dose-limiting adverse events. Finally, it was recently reported that the selective a4P2 nAChR partial agonist ABT-894 (structure not disclosed) that is also in development for pain, showed positive results in a Phase 2 study in adult ADHD patients with comparable efficacy to ► atomoxetine.
Selective nAChR agonists potentially represent a promising novel class of agents to treat neurodegenerative diseases (Rusted et al. 2000). AD is characterized by the presence of plaques containing ► amyloid-beta (AP) in the brain, which presumably contribute to neurodegeneration. Though there are conflicting reports in the literature, evidence suggests that AP can interact directly with a4P2- and a7-containing nAChRs, resulting in a functional blockade ofthese receptors. However, other reports suggest that some forms of AP can actually activate both a7 and non-a7 nAChRs. Although it appears that modulation of a7-con-taining nAChRs offers protection to neurons against AP-induced toxicity, the nature of these interactions and their relevance to AD need to be further investigated.
There is, however, substantial preclinical evidence that nAChR activation is neuroprotective against non-AP tox-icity induced by a variety of insults in AD. Although multiple nAChR receptor subtypes are likely involved, neuroprotection seems to be mediated mainly via a7 nAChRs. Activation of a7 nAChRs protects in vitro cell and slice preparations against ethanol toxicity and cell death; cultured neurons against glutamate-induced
► excitotoxicity; and hippocampal slices against oxygen and glucose deprivation. To date, there are no clinical study reports on the potential neuroprotective effects of selective nAChR ligands in AD.
Compelling epidemiologic evidence exists for an inverse relationship between tobacco use and incidence of
► Parkinson's Disease (PD), with smokers of the longest duration and highest daily consumption at the lowest risk of developing the disease. Though many interpretations for this relationship have been made, it seems unlikely to result from genetic factors for either PD or smoking. Indeed, the preponderance of data suggests that a component of tobacco, likely nicotine, offers a biological protection against neurodegeneration of dopaminergic neurons (Quiketal. 2008).
A hallmark feature of PD is loss of nigrostriatal dopa-mine function. Two nAChR populations are largely responsible for nicotine-evoked dopamine release in striatum: a4p2- and a6*-containing nAChRs. Though both populations appear to regulate dopamine release from the dopaminergic terminals, a6* nAChRs are more sensitive to nigrostriatal damage induced in animal models, generally paralleling other indices of nigrostrial degeneration. Declines in a4p2 nAChRs are also observed with disease progression, but this receptor population appears to be less sensitive than a6* nAChRs. Thus, targeting nAChRs appears to be a promising approach to protect against further nigrostriatal damage and to offer symptomatic relief by enhancing dopamine outflow.
Several small clinical studies have evaluated the effect of nicotine administered via smoking and/or NRT gum on the motor symptoms of PD (► Anti-Parkinson Drugs). However, evidence for the improvement of patients' status in these trials was at best modest and, in most cases, absent. Similarly, at least one clinical study has reported that the a4p2 agonist SIB-1508Y (Fig. 7) did not improve PD symptoms.
Although it is tempting to speculate that selective activation of a6* nAChRs may provide a greater opportunity for symptomatic relief, it is unclear if the progressive loss of the dopaminergic neurons that express this nAChR subtype would limit the therapeutic benefit for PD, especially in the later stages of the disease.
Preclinical pharmacologic studies have established that nicotine and several natural nicotinic compounds have analgesic effects that are attenuated by mecamylamine pretreatment. One example is the frog alkaloid epibati-dine (Fig. 8), which has received much attention as an extremely potent analgesic that binds with high affinity to several nAChR subtypes (Arneric et al. 2007). Involvement of a4p2-containing nAChRs in nociception is suggested by their presence in regions that modulate pain perception, and increased inhibitory GABAergic tone in the spinal cord (an analgesic mechanism) following a4p2 activation. Other nAChR subtypes may also be involved in the pain response, but have not yet been investigated in the same detail. In this respect, it is interesting to know that the nicotine metabolite nornicotine (Fig. 8), which is
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