Varenicline: The Newest Agent for Smoking Cessation

Lisa A. Potts; Candice L. Garwood


Am J Health Syst Pharm. 2007;64(13):1381-1384. 

In This Article

Chemistry and Pharmacology of Varenicline

Varenicline has a high affinity and high selectivity for binding at the α4ß2 receptor and is the first α4ß2 receptor partial agonist in its class. Varenicline is a highly water-soluble salt, similar in structure to nicotine, composed of a pyridine and pyrrolidine ring. Varenicline has a three-ring configuration with tetrahydro, methano, pyrizino, and benzapine components. Varenicline also binds with moderate affinity at the serotonin receptor, in part serving as the mechanistic rationale for the adverse effect of nausea that occurs with the agent.[10]

In vitro studies have shown that varenicline produces 68% of the response seen by the binding of nicotine to α4ß2 receptors. In vivo studies have found the dopamine response to varenicline to be 32-60% of the response to nicotine. With this partial agonist-antagonist profile, the varenicline molecule competitively inhibits nicotine, thereby blocking the effects of nicotine at the α4ß2 receptor site. Therefore, varenicline alleviates the symptoms of nicotine craving and withdrawal through its agonist activity while inhibiting the effects of repeated nicotine exposure by its antagonist activity.[5] Figure 1 illustrates varenicline's mechanism of action at the α4ß2 receptor site as a partial agonist.

Figure 1.

Varenicline's mechanism of action. (A) Nicotine from cigarettes stimulates the production of high levels of dopamine in terminal synapse in the nucleus accumbens. (B) No nicotine present, which induces a state of nicotine withdrawal. (C) Varenicline blocks the nicotine-receptor sites and partially agonizes the receptors, stimulating moderate levels of dopamine in the terminal synapse in the nucleus accumbens. Illustration by Marie Dauenheimer, CMI.


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