MPEP (2-methyl-6-(phenylethynyl)pyridine) was one of the first compounds found to act a selective antagonist for the metabotropic glutamate receptor subtype mGluR5. It was under development by Novartis in the late 1990's. MPEP was found to produce neuroprotective effects following acute brain injury in animals. MPEP was also found to have positive effects on animal models of depression, anxiety and morphine withdrawl.

S-(+)-niguldipine is a more active enantiomer and is a selective antagonist for the and α1A-adrenoceptor. In addition, it can be used for discriminating of alpha 1A- from alpha 1B-adrenoceptors. There were made attempts to investigate the antidepressant action of S-(+)-niguldipine on rats, but that studies were unsuccessful.

Hepzidine (BS 7051) is a compound, possessing antidepressive and anticholinergic properties.

Talopram (Lu 3-010) is a selective inhibitor norepinephrine transporter belonging to the antidepressants of the thymoleptic group.

Imiloxan is a highly selective alpha2B adrenoceptor antagonist and was developed for depression in the 1980s. In Phase 1 clinical trials imiloxan dosing led to hypersensitivity reactions; the molecule's development was discontinued.

Clorgiline is a monoamine oxidase (MAO) inhibitor. Specifically, it is an irreversible and selective inhibitor of MAO-A. Clorgiline was under investigation for antidepressant and anxiolytic potential but has never been marketed, likely due to efficacy concerns. It continues to see routine use as a molecular probe in biomedical research examining a number of neurological disease and cancer models. In addition to inhibiting the MAO-A receptor, it has also been found to bind to the sigma1 receptor, and with high affinity to the I2 imidazoline receptor.

Nisoxetine, 3-(o-methoxyphenoxy)-3-phenyl-N-methyl-propyl-amine, is a most active and selective inhibitor of norepinephrine uptake, which was developed by Eli Lilly as an antidepressant drug. It was shown that nisoxetine dose-dependently reduced acute food intake and the additive effect of it was preserved in obese mice. In addition, was revealed that nisoxetine produced local but not systemic analgesia against cutaneous nociceptive stimuli in rodents. However, this drug has no clinical applications in humans.

Diclofensine is an antidepressant with equipotent inhibitive effects on the neuronal uptake of norepinephrine (NE), serotonin, and dopamine. It is devoid of monoamine-releasing or monoaminoxidase-inhibiting properties. Diclofensine was found to be an effective antidepressant in human trials, with relatively few side effects, but was ultimately dropped from clinical development.

Fenmetozole is an alpha-2 adrenergic receptor antagonist which was developed for the treatment of schizophrenic and/or depressed patients, however never reached the market. It was also shown that the drug may reduce symptoms of minimal brain dysfunction in children and antagonize the effect of barbiturates and ethanol.

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.