Initial Cross-Over Test of A Positive Allosteric Modulator of Alpha-7 Nicotinic Receptors to Aid Cessation in Smokers With Or Without Schizophrenia

Abstract

Preclinical research shows that compounds acting at α7 nicotinic receptors (nAChRs) can reduce nicotine self-administration, suggesting that a positive allosteric modulator (PAM) of α7 receptors, JNJ-39393406, may aid smoking cessation. Moreover, individuals with schizophrenia, who have very high rates of smoking, have reduced expression of α7 nAChRs and may particularly benefit from this compound. In two parallel studies using a within-subject cross-over design, 36 healthy smokers (Study 1) and 62 smokers with schizophrenia (Study 2), both groups high in quit interest, attempted to initiate quitting temporarily during each of two 3-week phases. Treatments were the α7 nicotinic receptor PAM JNJ-39393406 (100 mg b.i.d.) or placebo (double-blind, counter-balanced). In each phase, all smoked ad lib with no drug on week 1 or during dose run-up on week 2, and then tried to quit every day during week 3. Abstinence (confirmed by CO <5 p.p.m.) and smoking reduction (CO <8), as well as cigarettes/day (in Study 1), were assessed daily (Monday-Friday) each quit week and compared between conditions. Secondary outcomes included abstinence symptoms (withdrawal and craving) and cognitive test responding (N-back; continuous performance task). In both studies, compared with placebo, active JNJ-39393406 did not increase the number of abstinent days nor reduce total smoking exposure. We also found no significant improvements in craving, withdrawal, or cognitive function. With this dose and study duration, our findings do not support further testing of this α7 nAChR PAM compound for possible efficacy in smoking cessation, in smokers with or without schizophrenia.

B-973, a Novel α7 nAChR Ago-PAM: Racemic and Asymmetric Synthesis, Electrophysiological Studies, and in Vivo Evaluation

“…However, despite all of these efforts, only limited success has been achieved clinically with galantamine (Figure ). JNJ-39393406 is an α7 PAM that is currently undergoing phase II clinical trials for depressive disorders and smoking cessation. , Most of the drug candidates that were pursued as α7 nAChR (partial) agonists or PAMs, however, failed in Phase II clinical trials for cognitive disorders due to insufficient efficacy. Recently, a unique class of compounds with dual modes of actionallosteric agonism and positive allosteric modulationhave been discovered and are referred to as “ago-PAMs” (e.g., GAT107, Figure ).…”

Impact of modulation of the α7 nicotinic acetylcholine receptor on nicotine reward in the mouse conditioned place preference test

“…Of importance, these compounds have been shown to interact in a similar fashion with human α7 receptors (Papke et al 2015; Quadri et al 2016; Timmermann et al 2007; Wang et al 2012), supporting the possible clinical benefits of these compounds. To our knowledge, there are only three published reports on PAMs in humans and these studies did not report any serious side effects (Gee et al 2017; Perkins et al 2018; Winterer et al 2013). Thus, PAMs and silent agonists may serve as useful complementary tools to understand the effect of α7 nAChR modulation in nicotine reward.…”

“…This is not due to lack of absorption, however, as systemic administration of NS1738 at similar doses produced brain concentrations (Freitas et al 2013b) that were shown to enhance the channel opening of acetylcholine in vitro (Timmermann et al 2007). Although these preclinical data suggest that stimulation of α7 nAChRs ought to reduce nicotine reward in smokers, it should be noted that JNJ-39393406, an α7 PAM, was shown to have no effect on smoking behaviors in humans (Perkins et al 2018). It is unclear from previous studies if JNJ-39393406 acts as a Type I α7 PAM, Type II α7 PAM, or both (Winterer et al 2013; Perkins et al 2018).…”

“…Although these preclinical data suggest that stimulation of α7 nAChRs ought to reduce nicotine reward in smokers, it should be noted that JNJ-39393406, an α7 PAM, was shown to have no effect on smoking behaviors in humans (Perkins et al 2018). It is unclear from previous studies if JNJ-39393406 acts as a Type I α7 PAM, Type II α7 PAM, or both (Winterer et al 2013; Perkins et al 2018). However, given the small sample size for healthy smokers, duration and the use of only one dose, this within subjects, cross-over design clinical study may not have sufficiently evaluated the effect of an α7 PAM on smoking behaviors.…”

Pharmacological Characterization of the Novel and Selective α7 Nicotinic Acetylcholine Receptor–Positive Allosteric Modulator BNC375

“…Type II PAMs, such as PNU120596, RO5126946, JNJ-1930942, and B-973, not only affect peak current but also delay receptor desensitization. So far, only a few a7 PAMs have progressed into clinical evaluation, including JNJ-39393406, which has advanced to phase 2 study for smoking cessation (Perkins et al, 2018), and AVL-3288, which has been evaluated in healthy human subjects for effects on neurocognitive performance (Gee et al, 2017).…”