BRL-44408, a potent (Ki=8.5 nM) and selective (>50-fold) α2A-adrenoceptor antagonist (KB=7.9 nM). BRL-44408 revealed antidepressant- and analgesic-like activity through selective alpha2A-adrenoceptor antagonism. Preclinical characterization of the neurochemical and behavioural profile of BRL-44408 suggests that selective antagonism of alpha2A-adrenoceptors may represent an effective treatment strategy for mood disorders and visceral pain. BRL-44408 increases hippocampal noradrenalin release following systemic administration. BRL-44408 has potential therapeutic application in the treatment of extrapyramidal side effects produced by some antipsychotic medications.

SB-228357 was originally developed by scientists at Smith Kline Beecham (now merged with Glaxo Welcome to form GlaxoSmithKline). SB-228357 was identified as an antagonist of the serotonin receptors 5-HT2a/b/c with the highest affinity exhibited towards the 5-HT2C receptor. SB-228357 was identified for preclinical development as a treatment for depression, anxiety, and cataplexy but has not progressed beyond animal trials.

Genipin is an aglycone derived from an iridoid glycoside called Geniposide (structure on the bottom) present in fruit of Gardenia jasmindides Ellis. Genipin have been demonstrated to have diverse pharmacological activities including anti-inflammatory, antioxidative, neuroprotective, and neurotrophic effects. Genipin is an excellent natural cross-linker for protein, collagen, gelatin, and chitosan cross-linking and can be considered as a substitute for glutaraldehyde. Due to cross-linking properties genipin can be used in controlling drug delivery. In addition genipin exerts choleretic action.

SB-224289 was originally developed by SmithKline, now known as GlaxoSmithKline. It was identified as an antagonist of the 5-hydroxytryptamine receptor 1B (5-HT1B) and subsequently investigated for potential antidepressant activity, although no human trials have been reported. Interestingly, SB-224289 was also found to exhibit antagonistic activity for the antifungal mechanism of Marine Depsipeptide Papuamide A in Candida albicans; although the specific mechanism of action remains unknown.

Lespedin (Kaempferitrin) is extracted in significantly high quantities from the leaves of Cinnamomum osmophloeum (C.O) and Bauhinia forficata, and are used as an antidiabetic herbal remedy in China and Brazil. Commercial product using dry Cinnamomum osmophloeum leaves has been sold locally in Taiwan. Oral administration of kaempferitrin reduced blood sugar in diabetic rats. Lespedin possessed significant antiosteoporotic activity. Combined with its limited estrogen-like side effect, Lespedin can be regarded as an idealistic antiosteoporotic candidate for human osteoporosis diseases. Kaempferitrin was found to have an acute lowering effect on blood glucose in diabetic rats and to stimulate the glucose uptake percentile, as efficiently as insulin in muscle from normal rats.

LY94939 was discovered as a result of efforts to develop agents that inhibit the uptake of 5-HT from the synaptic cleft. A selected analogue of LY94939, the compound LY82816 (3-p-trifluoromethyl-phenoxyN-methyl-3-phenylpropylamine oxalate or (fluoxetine oxalate), which was a secondary amine (later named as fluoxetine oxalate), and its primary amine or N-demethylated compound (later named as norfluoxetine), were the most potent inhibitors of [3 H]-5-HT uptake in nerve endings, with Ki values of 0.07 uM. The first salt form of fluoxetine tested in serotonin reuptake assays in the early 1970s was the oxalate salt (LY82816); however, the marketed version is the hydrochloride salt (fluoxetine hydrochloride (LY110140), or Prozac.

The selective serotonin reuptake inhibitor fluoxetine consists of equal amounts of R and S stereoisomers (antidepressant Prozac (racemic fluoxetine). Binding to the transporter confirmed selectivity of R- and S-fluoxetine for the 5-HT transporter versus the dopamine (DA) and norepinephrine (NE) human transporters. In addition, receptor binding studies demonstrated significant affinity of R-fluoxetine, but not S-fluoxetine, for human 5-HT(2A) and 5-HT(2C) receptor subtypes. R-fluoxetine acts as an antagonist at 5-HT(2A) and 5-HT(2C) receptors. The attempt to develop a single-enantiomer formulation of fluoxetine for the treatment of depression was unsuccessful. Eli Lilly has terminated its licensing and development agreement with Marlborough, Mass.-based Sepracor for (R)-fluoxetine, the single-isomer version of Lilly's antidepressant Prozac.R-enantiomer of fluoxetine, at its highest administered dose, led to statistically significant prolongation of cardiac repolarization in phase II studies; the studies were subsequently stopped.

Pseudohypericin is a predominant naphthodianthrone from St. John’s wort (Hypericum perforatum L.) phytomedicinal drug. It has been shown to specifically inhibit protein kinase C and dopamine-β-hydroxylase. Also, pseudohypericin induces apoptosis and selectively antagonizes corticotropin-releasing factor in murine models. Inhibition of thioredoxin system by pseudohypericin showed appreciable anticancer properties of this natural compound. Pseudohypericin has antiretroviral activity, it has potential therapeutic value in diseases such as AIDS. Pseudohypericin is implicated in the antidepressant efficacy of St. John's wort.

Norharman or beta-carboline (9H-pyrido[3,4-b]indole) is a neuroactive alkaloid first isolated from Peganum harmala L. It is implicated in a number of human diseases including Parkinson's disease, tremor, addiction and cancer. Norharman formed endogenously but external sources have been identified (among others fried meat and fish, meat extracts, alcoholic drinks, coffee brews, tobacco smoke). It inhibits monoamine oxidase and indoleamine 2,3-dioxygenase. In addition norharman binds with high affinity to imidazoline I2B receptors. Plasma norharman levels are elevated in chronic alcoholics and Parkinson's disease patients.

CP 154526 hydrochloride is a selective, non-peptide corticotropin releasing hormone receptor 1 (CRF1) antagonist. CP 154526 readily penetrates the CNS following peripheral administration. In the clinic, CP-154,526 may have important therapeutic utility in treating depression and anxiety as well as other diseases where excessive stimulation of CRF receptors contributes to pathology. The CRF1 receptor antagonist CP-154,526 attenuated the acquisition and prevented the expression of EtOH-induced psychomotor sensitization.