E-52862, also known as sigma-1 receptor antagonist (API-001, S1RA) successfully completed Phase I clinical trials for the treatment of pain, showing good safety and tolerability, and a pharmacokinetic profile compatible with once a day oral administration.

UR-144 is a potent synthetic cannabinoid designed by Abbott Laboratories as a CB2 selective agonist for pain management and other indications. UR-144 preferentially binds the peripheral CB2 receptor (Ki = 1.8 nM) over the central CB1 receptor (Ki = 150 nM). Pre-clinical studies of nociceptive and neuropathic pain have shown that CB2-selective ligands are analgesics without causing the adverse side effects linked with CB1 receptor activation. However, UR-144 has no therapeutic application. According to the FDA (US Food and Drug Administration) there are currently no approved or on-going drug applications for the medical use of UR-144.

N-((1S)-1-(Aminocarbonyl)-2-methylpropyl)-1-(5-fluoropentyl)-1H-indazole-3-carboxamide (5F-AB-PINACA) is an indazole-based synthetic cannabinoid developed by Pfizer in 2009 as an analgesic medication. In January 2015, AB-PINACA became a controlled substance in the USA and 5F-ABPINACA will be prohibited based on the analog law. 5F-AB-PINACA has been sold online as a designer drug.

N-MPPP HYDROCHLORIDE is high-affinity κ agonist with no measured binding at μ or δ sites.

J-113397 (ComB) is the first potent and selective small molecule ORL1 antagonist. Merck, in collaboration with Banyu, is developing J-113397 with potential use in the treatment of pain. Preclinical development is underway in Japan, however, no recent development has been reported. In addition to antinociceptive properties J-113397 exerts antiparkinsonian action in animal models.

HC-030031 is a substituted theophylline derivative. Potent and selective TRPA1 inhibitor. HC-030031 inhibits human and rat TRPA1 with IC50 of 6.2 and 7.6 uM, respectively. It is selective against several TRP channels (IC50 >10 or 20 uM). HC-030031 can block both inward and outward currents elicited by AITC or formalin rapidly and reversibly and also blocks the activation of TRPA1 by N-methylmaleimide and by electrophillic prostaglandins. It does not block currents mediated by TRPV1, TRPV3, TRPV4 hERG, or NaV1.2 channels. HC-030031 exhibited efficacy in CFA, SNL, and other pain models. HC-030031 was shown to attenuate cold hyperalgesia in CFA (inflammatory), spared never injury (SNI, neuropathic), and paclitaxelmediated cold hyperalgesia. Also HC-030031 was found to decrease heat hyperalgesia in the paclitaxel model of chemotherapy-induced neuropathic pain.In an ovalbumin-induced mouse asthma model, gene KO and treatment with HC-030031 reduced the induction of cytokines, chemokines, neurotransmitters, as well as leukocyte infiltration and airway hyperactivity. Furthermore, HC-030031 and genetic deletion of mast cells attenuated itch-scratching behaviors. In oxazolone-induced contact dermatitis models, TRPA1 KO and HC-030031 decreased pro-inflammatory cytokines, T cell infiltration, dermatitis score, and edema, indicating that TRPA1 may play a central role in inflammation and pruritus.

Verticinone is a major alkaloid isolated from the bulbus of Fritillaria ussuriensis. Verticinone was rapidly absorbed, widely distributed in most tissues, and metabolized extensively before excretion. Verticinone has antitumor effects - treatment with verticinone can induce cancer cell apoptosis and autophagy via modulating the production of metabolites, which are supportive of carcinoma cell proliferation. Due to the potent antitussive activity and no addictive effect, verticinone seems to be a promising potential antitussive drug. Verticinone is expected to become a potentially novel sedative-analgesic agent without producing tolerance and dependence.

A-784168 is a potent and selective antagonist of Vanilloid receptor type 1 (TRPV1). A-784168 has a good CNS penetration. Significant CNS penetration is necessary for a TRPV1 antagonist to produce broad-spectrum analgesia that was shown on animal models after oral administration of this compound.

A-803467 is a selective NaV1.8 channel blocker with IC50 of 8 nM, blocks tetrodotoxin-resistant currents, exhibits >100-fold selectivity against human NaV1.2, NaV1.3, NaV1.5, and NaV1.7. A-803467 reduces behavioral measures of chronic pain. Systemic administration of A-803467 demonstrated acute antinociceptive activity as measured as a reduction in mechanical allodynia in several models of inflammatory and neuropathic pain in rats. Additionally, systemic and intraspinal delivery of A-803467 attenuates both evoked and spontaneous firing of wide dynamic range neurons in rats with spinal nerve ligations.

Racemic phenibut (beta-phenyl-gamma-aminobutyric acid or 4-amino-3-phenylbutyric acid) is a neuropsychotropic drug that was discovered and introduced into clinical practice in Russia in the 1960s. In pharmacological tests of locomotor activity, antidepressant and pain effects, S-phenibut was inactive. In contrast, R-phenibut turned out to be two times more potent than racemic phenibut in most of the tests. Racemic phenibut and R-phenibut demonstrated an affinity for GABAB receptors, in contrast, S-phenibut was not able to bind receptors. Pharmacological activity of racemic phenibut relies on R-phenibut and this correlates to the binding affinity of enantiomers of phenibut to the GABAB receptor. Both S- and R-phenibut bind to the α2-δ subunit of voltage-dependent calcium channels and exert gabapentin-like anti-nociceptive effects. In addition S-isomer was found to be a substrate of gamma-aminobutyric acid aminotransferase, however, the R-isomer is a competitive inhibitor.