Pharmacodynamics Atypical μ-opioid receptor agonist In 2014, tianeptine was found to be a
μ-opioid receptor (MOR)
full agonist using human proteins. It was also found to act as a full agonist of the
δ-opioid receptor (DOR), although with approximately 200-fold lower potency. Moreover, in mice, although tianeptine produced other
opioid-like behavioral effects such as
analgesia and
reward, it did not result in
tolerance or
withdrawal. In addition to its therapeutic effects, activation of the MOR is likely to also be responsible for the
abuse potential of tianeptine at high doses that are well above the normal therapeutic range and efficacy threshold. In rats, when co-administered with morphine, tianeptine prevents morphine-induced
respiratory depression without impairing analgesia. In humans, however, tianeptine was found to increase respiratory depression when administered in conjunction with the potent opioid
remifentanil.
Glutamatergic, neurotrophic, and neuroplastic modulation Research suggests that tianeptine produces its antidepressant effects through indirect alteration and inhibition of
glutamate receptor activity (i.e.,
AMPA receptors and
NMDA receptors) and release of , in turn affecting
neural plasticity. Tianeptine had been found to bind to the same
allosteric site on the
serotonin transporter (SERT) as conventional TCAs. However, whereas conventional TCAs
inhibit serotonin reuptake by the SERT, tianeptine appeared to enhance it. The (−)-
enantiomer is more active in this sense than the (+)-enantiomer. However, more recent studies found that long-term administration of tianeptine does not elicit any marked alterations (neither increases nor decreases) in extracellular levels of serotonin in rats. In any case, the collective research suggests that direct modulation of the serotonin system is unlikely to be the
mechanism of action underlying the antidepressant effects of tianeptine. and potentiates
CNS D2 and
D3 receptors. Tianeptine has no affinity for the
dopamine transporter or the
dopamine receptors. is a cellular
transcription factor. It binds to certain
DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the
transcription of the
genes. CREB has a well-documented role in
neuronal plasticity and
long-term memory formation in the brain. Cocaine- and amphetamine-regulated transcript, also known as
CART, is a
neuropeptide protein that in humans is encoded by the
CARTPT gene. CART appears to have roles in reward, feeding, stress, and it has the functional properties of an endogenous
psychostimulant. Taking into account that CART production is upregulated by CREB, it could be hypothesized that due to tianeptine's central role in BDNF and neuronal plasticity, this CREB may be the transcription cascade through which this drug enhances mesolimbic release of dopamine. Research indicates possible
anticonvulsant (anti-seizure) and
analgesic (painkilling) activity of tianeptine via downstream modulation of
adenosine A1 receptors (as the effects could be experimentally blocked by
antagonists of this receptor). Tianeptine has been shown to be a high-efficacy agonist of
PPAR-delta, a nuclear receptor.
Pharmacokinetics The
bioavailability of tianeptine is approximately 99%. In 2022 Tonix Pharmaceuticals received permission from the US FDA to conduct phase II clinical trials on tianeptine hemioxalate extended-release tablets designed for once-daily use. The project was discontinued in late 2023 because of disappointing results in
clinical trials. Tianeptine has two
active metabolites, MC5 (a
pentanoic acid derivative of the parent compound) and MC3 (a
propionic acid derivative). MC5 has a longer elimination half-life of approximately 7.6 hours, and takes about a week to reach steady-state concentration under daily-dosing. MC5 is a mu-opioid agonist but not delta-opioid agonist, with
EC50 at the mu-opioid receptor of 0.545 μM (vs 0.194 μM for tianeptine). MC3 is a very weak mu-opioid agonist, with an EC50 of 16 μM. Tianeptine is
excreted 65% in the
urine and 15% in
feces. ==Chemistry==