Pharmacodynamics +<unk>  Site Ki (nM) Species Ref 383–768 (Ki)194 () Human >10,000 (Ki)37,400 () Human >10,000 (Ki)100,000 () Human >10,000 Human >10,000 Human >10,000 Human 5-HT1A >10,000 Human 5-HT1B >10,000 Human 5-HT1D >10,000 Human 5-HT1E >10,000 Human 5-HT2A >10,000 Human 5-HT2B >10,000 Human 5-HT2C >10,000 Human 5-HT3 >10,000 Human 5-HT5A >10,000 Human 5-HT6 >10,000 Human 5-HT7 >10,000 Human α1A >10,000 Human α1B >10,000 Human α2A >10,000 Human α2B >10,000 Human α2C >10,000 Human β1 >10,000 Human β2 >10,000 Human D1 >10,000 Human D2 >10,000 Human D3 >10,000 Human D4 >10,000 Human D5 >10,000 Human H1 >10,000 Human H2 >10,000 Human H3 >10,000 Human H4 >10,000 Human >10,000 Human σ1 >10,000 Guinea pig σ2 >10,000 Rat I1 >10,000 Human A1 >10,000 () Human >10,000 Human Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug interacts with the site. Atypical μ-opioid receptor agonist In 2014,<unk>  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. The same researchers subsequently found that the MOR is required for the acute and chronic antidepressant-like behavioral effects of<unk>  in mice and that its primary metabolite had similar activity as a MOR agonist but with a much longer elimination half-life. Moreover, although<unk>  produced other opioid-like behavioral effects such as analgesia and reward, it did not result in tolerance or withdrawal. The authors suggested that<unk>  may be acting as a biased agonist of the MOR and that this may be responsible for its atypical profile as a MOR agonist. However, there are reports that suggest that withdrawal effects resembling those of other typical opioid drugs (including but not limited to depression, insomnia, and cold/flu-like symptoms) do manifest following prolonged usage of dose usage far beyond the medical range. In addition to its therapeutic effects, activation of the MOR is likely to also be responsible for the abuse potential of<unk>  at high doses that are well above the normal therapeutic range and efficacy threshold. When co-administered with morphine,<unk>  prevents morphine-induced respiratory depression without impairing analgesia. Glutamatergic, neurotrophic, and neuroplastic modulation Research suggests that<unk>  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. Some researchers hypothesize that<unk>  has a protective effect against stress induced neuronal remodeling. There is also action on the NMDA and AMPA receptors. In animal models,<unk>  inhibits the pathological stress-induced changes in glutamatergic neurotransmission in the amygdala and hippocampus. It may also facilitate signal transduction at the CA3 commissural associational synapse by altering the phosphorylation state of glutamate receptors. With the discovery of the rapid and novel antidepressant effects of drugs such as ketamine, many believe the efficacy of antidepressants is related to promotion of synaptic plasticity. This may be achieved by regulating the excitatory amino acid systems that are responsible for changes in the strength of synaptic connections as well as enhancing BDNF expression, although these findings are based largely on preclinical studies. Serotonin reuptake enhancer<unk>  is no longer labelled a Selective Serotonin Reuptake Enhancer (SSRE) antidepressant.<unk>  has 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,<unk>  appears to enhance it. This seems to be because of the unique C3 amino heptanoic acid side chain of<unk> , which, in contrast to other TCAs, is thought to lock the SERT in a conformation that increases affinity for and reuptake (Vmax) of serotonin. As such,<unk>  acts as a positive allosteric modulator of the SERT, or as a "serotonin reuptake enhancer". Although<unk>  was originally found to have no effect in vitro on monoamine reuptake, release, or receptor binding, upon acute and repeated administration,<unk>  decreased the extracellular levels of serotonin in rat brain without a decrease in serotonin release, leading to a theory of<unk>  enhancing serotonin reuptake. The (−)-enantiomer is more active in this sense than the (+)-enantiomer. However, more recent studies found that long-term administration of<unk>  does not elicit any marked alterations (neither increases nor decreases) in extracellular levels of serotonin in rats. However, coadministration of<unk>  and the selective serotonin reuptake inhibitor fluoxetine inhibited the effect of<unk>  on long-term potentiation in hippocampal CA1 area. This is considered an argument for the opposite effects of<unk>  and fluoxetine on serotonin uptake, although it has been shown that fluoxetine can be partially substituted for<unk>  in animal studies. 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<unk> . Other actions<unk>  modestly enhances the mesolimbic release of dopamine and potentiates CNS D2 and D3 receptors.<unk>  has no affinity for the dopamine transporter or the dopamine receptors. CREB-TF (CREB, cAMP response element-binding protein) 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 an 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<unk> '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<unk>  via downstream modulation of adenosine A1 receptors (as the effects could be experimentally blocked by antagonists of this receptor).<unk> npetine is also weak histone deacetylase inhibitor and analogs with increased potency and selectivity are developed. Pharmacokinetics The bioavailability of<unk>  is approximately 99%. Its plasma protein binding is about 95%. The metabolism of<unk>  is hepatic. Its elimination half-life is 2.5 to 3 hours. The elimination half-life has been found to be increased to 4 to 9 hours in the elderly. The drug has an active metabolite, with a much longer elimination half-life of approximately 7.6 hours, leading to a steady-state after about a week.<unk>  is excreted 65% in the urine and 15% in feces.
Tianeptine
Droperidol
Galantamine
Rivastigmine
Cupiennin
Gliquidone
Tripelennamine
Bromperidol decanoate