CTEP is a compound chemically derived from basimglurant and optimized for utility in rodent studies. CTEP is the first reported mGlu5 inhibitor with both, very long half-life and high oral bioavailability in rodents, classifying as useful pharmacological tool for long-term treatment. CTEP is significantly active in treatment of anxiety in rat and mouse. Chronic treatment with CTEP in a mouse model of Fragile X rescued learning and memory deficits, elevated locomotor activity and increased spine density, suggesting that this treatment may be effective in correcting multiple neurological symptoms. CTEP was able to improve various behavioral alterations induced by chronic social defeat stress.

Sazetidine-A (6-[5-(azetidin-2-ylmethoxy)pyridin-3-yl]hex-5-yn-1-ol or AMOP-H-OH) is a "silent desensitizer" of neuronal nicotinic acetylcholine receptors (nAChRs), meaning that it desensitizes the receptor without first activating it. Later it was shown that Sazetidine-A is an agonist of native and recombinant alpha4beta2 nAChRs but shows differential efficacy on alpha4beta2 nAChRs subtypes. In animal models it is able to regulate the gain in body weight, alcohol and nicotine dependence. Sazetidine-A exerts analgesic, antidepressant and anxiolytic properties.

DOV-102,677 is a “Triple” Monoamine Neurotransmitter Uptake Inhibitor being developed by Merck for treating the major depressive disorder. In preclinical studies, DOV 102,677 increased extracellular levels of DA and 5-HT in the prefrontal cortex at 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 240 min post-dosing. Consistent with these increases in NE levels, the density of β-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. However, phase I clinical trials for treatment Depression in the USA was discontinued. Instead of being developed for depression, DOV-102,677 is being developed for the treatment of alcoholism.

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.

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.

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.

Norketamine is one of the major metabolites of Ketamine, which is routinely used as an anesthetic. Norketamine is a potent antagonist of the N-methyl-D-aspartate receptor and is believed to contribute to the analgesic effects of ketamine. In animal models, norketamine has been noted to increase the glomerular filtration rate by remodeling the cellular cytoskeleton, and it has been identified as having possible antidepressant effects.

SKF83959 is a benzodiazepine derivative which acts as an agonist of D1 receptor. Activation of D1 receptors by SKF83959 fails to stimulate adenylyl cyclase and inhibits the stimulation of adenylyl cyclase induced by dopamine but stimulates phosphatidylinositol 4,5-biphosphate hydrolysis in membranes of frontal cortex. SKF83959 was identified as a specific agonist for the heteromer D1/D2 complex. SKF83959 elicit anti-parkinsonism effects in monkeys and rodents. In lower concentrations, SKF83959 inhibits serotonin, norepinephrine and dopamine transporters and is an allosteric regulator of sigma 1 receptor. The compound has demonstrated activity in a preclinical model of depression.

ICI-63197 is a potent and selective phosphodiesterase IV (PDE 4) inhibitor with potent antidepressant activity. The antidepressant action of ICI-63197 realizes via enhancement of central noradrenergic transmission due to selective inhibition of cAMP phosphodiesterase. ICI 63 197 was investigated in mice for its effectiveness in two classical test models for prediction of clinical antidepressant activity: antagonism of reserpine-induced hypothermia or hypokinesia and potentiation of yohimbine lethality. ICI 63 197 was approximately 15 times more potent than imipramine in antagonizing reserpine-induced hypothermia. The antihypothermic effect of the ICI-63197 occurred at a smaller dose than that of imipramine. In contrast to imipramine, the ICI-63197 reversed reserpine-induced hypokinesia. ICI-63197 approximately, as potent as imipramine in potentiating the lethality of yohimbine. ICI 63 197 was never tested in clinical trials.

GW-803430 is centrally active and selective antagonist of melanin-concentrating hormone receptor (MCHR) 1. GlaxoSmithKline was developing orally active, potent and selective GW-803430 for the treatment of obesity. GW803430 produces robust antiobesity and antidepressant-like effects in rodents.