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 ß2-containing (i.e., ß2*) nAChRs (e.g., a4ß2, a6ß2)8, because ß2 subunits are required for the
maintenance of nicotine self-administration9, while re-expression of ß2 subunits in the VTA of ß2 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 a7 subtype of nAChRs. Activation of a7 nAChRs inhibits
nicotine rewarding effects in conditioned place preference (CPP) and self-administration models of nicotine
dependence in mice.11,12 Thus, a7 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 a7 agonist and
partial ß2 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 a7 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 a7 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.