- SmokeLESS (varenicline) selectively binds more potently to α4β2 nicotinic acetylcholine receptors (nAChRs) in the brain, than to other common nicotinic receptors (>500-fold α3β4, >3500-fold α7, >20,000-fold α1βγδ), or to nonnicotinic receptors and transporters (>2000-fold).
“The α4β2 receptor subtype is thought to mediate the rewarding properties of nicotine by modulating the release of dopamine in the nucleus accumbens, the so called "pleasure centre" of the brain (see diagram)”.

- By binding to α4β2 nicotinic acetylcholine receptors (nAChRs)in the brain, SmokeLESS (varenicline) provides dual effects: 

ACTION 1: AGONIST EFFECT
SmokeLESS binds to, and partially stimulates, the receptor without creating a full nicotine effect on the release of dopamine.
"Agonist" means that when varenicline binds to the nicotinic receptor it has an effect similar to that of nicotine in stimulating the release of dopamine, although varenicline produces a slower, longer lasting and smaller increase in dopamine release than nicotine. Thus it partially mimics the effect of nicotine and this is thought to explain why it reduces craving when smokers abstain and are deprived of nicotine.

ACTION 2: ANTAGONIST EFFECT
Because SmokeLESS competitively binds to α4β2 receptors, it blocks the ability of nicotine to stimulate the central nervous mesolimbic dopamine system, believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking.
Because varenicline doesn't have as strong an effect as nicotine in releasing dopamine, the addiction potential is likely to be lower.

NICOTINE — FULL AGONIST ACTION

1- Nicotine binds to the receptor, stimulating the release of dopamine, for a full agonist effect.
2- Research demonstrates that α4β2 nAChRs in the brain play a principal role in mediating reinforcement- and dependence-producing effects of nicotine.
3- SmokeLESS produces a partial agonist effect.
4- SmokeLESS produces an antagonist effect.

SmokeLESS — PARTIAL AGONIST ACTION

Thus, SmokeLESS demonstrates
a Novel Combination of Agonist and Antagonist Effects
in Smoking Cessation