6-Hydroxyflavone is a naturally occurring flavone found in the leaves of Barleria prionitis, a plant species in the Acanthaceae family native to India that is widely used against neurological disorders such as paraplegia, sciatica, etc. 6-Hydroxyflavone partially potentiated GABA-induced currents in native GABAA receptors expressed in cortical neurons via BZ site, as the enhancement was blocked by the antagonist flumazenil. Furthermore, in patch clamp studies, 6-Hydroxyflavone displayed the significant preference for a2- and a3- containing subtypes, which were thought to mediate anxiolytic effect, compared to a1- and a5- containing subtypes expressed in HEK 293T cells. In mice, 6-Hydroxyflavone exhibited the anxiolytic-like effect in the elevated plus-maze test, unaccompanied at anxiolytic doses by the sedative, cognitive impairing, myorelaxant, motor incoordination and anticonvulsant effects commonly associated with classical BZs when tested in the hole-board, step-through passive avoidance, horizontal wire, rotarod, and pentylenetetrazol (PTZ)-induced seizure tests, respectively. The findings, therefore, identified 6-Hydroxyflavone as a promising drug candidate for the treatment of anxiety-like disorders.

Bufotenine is a hallucinogenic serotonin analog found in frog and toad skins, mushrooms, plants and some mammals (especially in the brains, plasma, and urine of schizophrenics). It

(E)-2-decenoic acid is a stereoisomer of the corresponding medium-chain fatty acid in the trans configuration. This compound excreted by the caries bacterium Streptococcus mutants and inhibits the morphological transition from yeast to hyphae, an important virulence trait, in the opportunistic fungus Candida albicans. As a component of royal jelly it exhibits estrogenic effect by activation of estrogen receptor beta. Ethyl ester of trans-2-decenoic acid exerts neurotrophin-like neurotrophic activities in animal models of stress-induced anxiety-like, cerebral infarction and spinal cord injury.

BMY-7378 is a multi-targeted inhibitor of α2C-adrenoceptor and α1D-adrenoceptor with pKi of 6.54 and 8.2, respectively, and acts as a mixed agonist and antagonist for 5-HT1A receptor with pKi of 8.3. BMY-7378 was at the preclinical stage of development for the treatment of anxiety disorders, but later was discontinued.

Zolantidine is the novel benzthiazole derivative. It is a centrally acting potent antagonist of histamine at H2-receptors. It was found to be a competitive inhibitor of the histamine catabolising enzyme in brain, histamine N-methyltransferase. High aggression in histamine N-methyltransferase knockout mice was suppressed by treatment with zolantidine, indicating that abnormal histamine H2 receptor activation promoted aggression in knockout mice. Histamine H(3) receptor antagonist JNJ-10181457-induced anxiety-like behaviours were dominantly reduced by zolantidine. Zolantidine significantly attenuated the discriminative stimulus effects of morphine.

Magnoflorine is a chemical compound isolated from the rhizome of Sinomenium acutum and from Pachygone ovata. Magnoflorine was shown to suppress the induction phase of the cellular immune response, and assigned as noncytotoxic to various human cancer cell lines. In addition, it was shown that Sinomeni Caulis et Rhizoma has sedative and anxiolytic effects, probably mediated by magnoflorine through a GABAergic mechanism of action. Moreover, magnoflorine can protect the erythrocyte membrane from LPC-induced damage, which was demonstrated in experiments on rat erythrocytes. This protective effect is mediated by some mechanism other than prevention of micelle formation or protection of the erythrocyte membrane against osmotic imbalance.

Sinapic acid is one of the most common hydroxycinnamic acids and is widespread in the plant kingdom. It has been identified in various fruits, vegetables, cereal grains, oilseed crops, some spices, and medicinal plants. Sinapic acid and its derivatives possess antimicrobial, antioxidant, anti-inflammatory, anticancer and anti-anxiety activities.

MRK-409 (MK-0343) is a subtype-selective GABA(A) partial agonist that occupies the benzodiazepine site of GABA(A) receptors. MK-0343 was designed to be a less sedating anxiolytic, based on reduced efficacy at the alpha-1 subtype and significant efficacy at alpha -2 and alpha-3 subtypes of the GABA(A) receptor. MRK-409 binds to alpha-1, 2, 3 and 5-containing human recombinant GABA(A) receptors with comparable high affinity (0.21-0.40 nM). However, MRK-409 has greater agonist efficacy at the alpha-3 compared with alpha-1 subtypes. MRK-409 exhibited anxiolytic and non-sedating properties in different rodent and primate models of unconditioned and conditioned models of anxiety but produced sedation in man at relatively low levels of GABA(A) receptor occupancy (∼10%). It was suggested that the sedation with MRK-409 was due to the partial agonist efficacy of that compound at the alpha-1 subtype. Although MRK-409 (MK-0343) reached clinical studies its development had to be stopped due to sedative effects in humans demonstrated that more preclinical efforts are needed to identify compounds with improved selectivity.

L-760735 is a non-peptide substance P receptor (Neurokinin 1 (NK1) receptor) antagonist. It exerts anxiolytic, antidepressant and antinociceptive actions in animals. Merck was developing an L- 760735 as a potential antidepressant.

CGS-20625 is a potent and selective ligand for the central benzodiazepine receptor. It acts as a partial agonist of GABAA channel in vitro and produces anxiolytic and anticonvulsant effects in vivo. The drug has low bioavailability so its clinical applications are limited, and it is mainly used as a tool compound.