Mitragynine is the main active alkaloid constituent of the plant Mitragyna speciosa Korth. Mitragyna speciosa Korth. (M. speciosa), from the Rubiaceae family, is a tropical medicinal plant native to Southeast Asia. In Malaysia, M. speciosa leaves are known as Ketum or Biak, and in Thailand as Kratom. M. speciosa has been historically used in Southeast Asia as a stimulant drug and in its traditional context as a remedy for various symptoms. Pharmacological activities are mainly mediated via opioid receptors as well as neuronal Ca2+ channels, expression of cAMP and CREB protein and via descending monoaminergic system. Mitragynine acted as a partial agonist at mu-opioid receptors, in contrast, at kappa-opioid receptors, mitragynine was a competitive antagonist, similarly, mitragynine acted as an antagonist at delta-mu-opioid receptors, but with very low potency. Experimental studies in animals have now shown that mitragynine has an addictive potential, however, only at higher doses. Human users in countries of frequent use with a traditional context report a rather low daily consumption with only mild side effects. Kratom and mitragynine can be instrumentalized to enhance physical work power and endurance. A major reason for Kratom consumption is its reported efficacy to replace opiates in chronic users. This makes the Kratom plant preparation and also the isolated compound mitragynine interesting options to treat opiate addiction. In August 2016, the US Drug Enforcement Administration announced plans to classify kratom and its mitragynine constituents as Schedule 1 controlled substances.

BI-D1870 is a small molecule, which inhibits RSK1, RSK2, RSK3 and RSK4 in vitro with an IC(50) of 10-30 nM, but does not significantly inhibit ten other AGC kinase members and over 40 other protein kinases tested at 100-fold higher concentrations. BI-D1870 is cell permeant and prevents the RSK-mediated phorbol ester- and EGF (epidermal growth factor)-induced phosphorylation of glycogen synthase kinase-3beta and LKB1 in human embryonic kidney 293 cells and Rat-2 cells. BI-D1870 exhibited a dose-responsive antiproliferative effect on OSCC cells with relative sparing of normal human oral keratinocytes. The compound inhibited the downstream RSK target YB-1 and caused apoptosis. In addition, BI-D1870 also induced G2/M arrest by modulating the expression of p21 and other cell cycle regulators. BI-D1870 may be of useful in oral squamous cell carcinoma therapy. BI-D1870 has being shown to ameliorate experimental autoimmune encephalomyelitis in mice. BI-D1870 administration protected mice from EAE by reducing the infiltration of TH1 and TH17 cells into the CNS and decreasing mRNA levels of Ccr6 in TH17 cells. These results suggest that RSK inhibition is a promising strategy for the treatment of MS.

WAY 208466 dihydrochloride is a high affinity, selective SR-6 (5-HT6) receptor agonist. WAY-208466 produced both antidepressant-like and anxiolytic-like effects. Direct infusion of WAY-208466 into the dorsal raphe nucleus, locus coeruleus, basal forebrain (horizontal limb of the diagonal band of Broca) or laterodorsal tegmental nucleus specifically decreased REM sleep without significantly altering wakefulness or slow wave sleep.

PF-514273 is a drug developed by Pfizer, which acts as an extremely selective antagonist for the CB1 receptor, with approximately 10,000x selectivity over the closely related CB2 receptor. Pfizer was developing PF 514273 in phase I clinical studies for the treatment of obesity in the US. However, these studies were discontinued.

DB09173 (Butyrfentanyl or butyrylfentanyl) is a potent, short-acting mu opioid receptor agonist, and an analog of fentanyl, differing by only one methyl group. It has no approved medical indications but is being used for recreational purposes, with cases of fatal overdoses reported in Europe and the United States. Pre-clinical studies of butyrfentanyl are scarce; however, the few available studies suggest that butyrfentanyl is about 30 times less potent than fentanyl itself, and has significant antinociceptive properties, as demonstrated by the acetic acid writhing test in rodents. DB09173 is being abused for its opioid effects. As with other mu-opioid agonists, it can induce respiratory depression which may lead to death and numerous deaths have been reported. No studies of butyrfentanyl dependence or cross-dependence conducted in humans could be identified.

Ginsenoside Rb3 is a protopanaxadiol ginsenoside that can be isolated from several different Panax species. Ginsenoside Rb3 exerts antidepressant and antidiabetic activities as well as cardio- and neroprotective action in ischemic tissue injury in animal models. Ginsenoside Rb3 inhibits apoptosis and cell proliferation, in addition it demonstrates antiaxidant properties. Ginsenoside Rb3 may modulate activity of GABA-A and NMDA receptors.

ASP-2535 is a glycine transporter-1 (GlyT1) inhibitor which was developed by Astellas Pharma for the treatment of Schizophrenia and Alzheimer's disease. Although ASP-2535 was shown to improve cognitive impairment in animal models, it is no longer in the company pipeline.

LY-300168 (GYKI-53655) is a negative allosteric AMPA modulator. It is used as a tool compound to study role of AMPA receptor in CNS functioning. Administration of LY-300168 demonstrated anxyolitic effects. GYKI-53655 produced a dose-dependent prolongation of survival time in the MgCl2 induced global ischaemia model.

MS 245 oxalate represents the first member of a novel class of reasonably selective tryptamine-based 5-HT6 receptor antagonists. MS 245 potentiated the hypolocomotor actions, but not the antinociceptive effects, of (-)nicotine in mice. MS 245 together with the ED50 dose of (+)amphetamine resulted in dose-related stimulus generalization. In contrast, the administration of various doses of MS-245 in combination with the ED50 dose of cocaine failed to result in stimulus generalization.

alpha-yohmbine (aka rauwloscine) is a diastereomer of yohimbine and shares many of the same properties. Rauwolscine acts as an alpha-2-adrenergic antagonist and is therefore used as an unregulated nutritional supplement for fat-burning and CNS stimulation. Rauwolscine is also an antagonist of the HT2B receptor and has been investigated for the potential to mitigate blood vessel spasms.