Classics in Chemical Neuroscience: Tianeptine

Abstract

Tianeptine (1) is an unusual antidepressant in that its mechanism of action appears to be independent from any activity at serotonin receptors or monoamine transporters. In fact, tianeptine has been shown to be a moderately potent agonist for the mu opioid receptor (MOR) and to a lesser extent the delta opioid receptor (DOR). Additionally, tianeptine's efficacy may be related to its action on glutamate-mediated pathways of neuroplasticity. Regardless of which neurotransmitter system is primarily responsible for the observed efficacy, the MOR agonist activity is problematic with respect to abuse liability. Increasing numbers of case reports have demonstrated that tianeptine is indeed being used recreationally at doses far beyond what are considered therapeutically relevant or safe, and scheduling reclassifications or outright bans on tianeptine products are ongoing around the world. It is the aim of this review to discuss the medicinal chemistry and pharmacology of tianeptine and to summarize this intriguing discrepancy between tianeptine's historical use as a safe and effective antidepressant and its emerging potential for abuse.

Keywords: antidepressant; drug abuse; opioid; serotonin; tianeptine.

Figure 1

Chemical structures of tianeptine and selected FDA-approved antidepressants.

Scheme 1. Initial Synthesis of Tianeptine (Top), and Modification of the Synthesis for Improved Yield (Bottom)

Figure 2

X-ray crystal structure of tianeptine hydrochloride. Reprinted with permission from ref (26). Copyright 2012 IUCr Journals.

Figure 3

Selected recent examples of known modifications to the tianeptine scaffold.

Figure 4

Tianeptine SAR from reserpine-induced ptosis.

Figure 5

Summary of SAR findings for tianeptine and analogs at the MOR.

Scheme 2. Metabolic Pathways of Tianeptine

Figure 6

Examples of products containing tianeptine. Such products are often labeled in a misleading manner; see the “turmeric supplement” on the right-hand side. Photos courtesy of the FDA’s Office of Regulatory Affairs, Health Fraud Branch.

Figure 7

Global case reports of tianeptine abuse.