Research Project
10107679
Project Summary/Abstract Nicotine addiction is associated with elevated release of dopamine in brain reward centers of the striatum and the basal forebrain including the nucleus accumbens (NAc) synapsed by dopaminergic neurons of the ventral tegmental area (VTA) and the substantia nigra (SN) of the midbrain.1-3 Nicotine is a potent psychostimulant whose addictive potential originates from modulation of activity of dopaminergic VTA and SN neurons resulted from activation of nicotinic acetylcholine receptors (nAChRs) expressed in these neurons in high densities.1,2,4 Because nAChRs are non-selective cation channels5, stimulation of nAChRs6,7 by nicotine excites midbrain dopaminergic neurons, stimulates the mesostriatal projections and elevates release of dopamine in the basal forebrain and the striatum commencing nicotine reinforcement.2,4,8 Studies utilizing rodent models of nicotine rewarding efficacy indicated that the addictive potential of nicotine is primarily linked to activation of ?2-containing (i.e., ?2*) nAChRs (e.g., ?4?2, ?6?2)8, because ?2 subunits are required for the maintenance of nicotine self-administration9, while re-expression of ?2 subunits in the VTA of ?2 knock-out mice reinstates nicotine self-administration behavior in mice10. The other key player in nicotine reinforcement and a promising target in nicotine cessation therapies is the ?7 subtype of nAChRs. Activation of ?7 nAChRs inhibits nicotine rewarding effects in conditioned place preference (CPP) and self-administration models of nicotine dependence in mice.11,12 Thus, ?7 selective agonists and positive allosteric modulators (PAMs) may prove to be valuable as potential treatments in smoking cessation therapies.13 Accordingly, the only two FDA-approved drugs, varenicline and bupropion, directly interact with central nAChRs:14 varenicline is a full ?7 agonist and partial ?2 agonist15,16, while less effective, bupropion, is a non-selective nAChR antagonist and an inhibitor of dopamine uptake14,17. A major problem in the treatment of nicotine addiction is relapse.20 Despite being clinically safe and effective for smoking cessation14,18, both varenicline and bupropion allow for high relapse rates at 1 year of treatment.17,19-21 Both drugs also cause a number of side effects including nausea22, constipation23 and insomnia17 that may reduce treatment adherence14. Bupropion is also contraindicated for people with seizures.14 Thus, the rationale for this proposal arises from the critical need for safe novel ?7 ligands that inhibit nicotine rewarding effects and produce superior treatment adherence and relapse rates. We hypothesize that these superior therapeutic properties may be offered by PAMs, a class of selective ?7 ligands24. Importantly, a recent study in mice demonstrated significant inhibition of nicotine reinforcement in the nicotine CPP test12 suggesting that endogenous cholinergic tone is sufficient to engage PAM-dependent therapeutic mechanisms with significant inhibitory efficacy for nicotine rewarding effects. The goal of this project is to optimize and develop a lead compound based on EPGN1137, a novel PAM identified that is effective in pre-clinical models of stroke. Limited medicinal chemistry will be conducted to identify 2 leads with appropriate drug like properties suitable for in vivo administration, including metabolic stability, minimized drug interaction risk and suitable pharmacokinetic profile. Pre-clinical efficacy testing will be conducted at University North Texas Health Sciences Center in rats on the leads to establish inhibition of nicotine reward and validate this chemical class as a potential therapeutic option for the treatment of nicotine abuse.
