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.

PK-11195 was first discovered by Pharmuka Laboratories. It was found to be antagonist of the Translocator Protein (TSPO) with potential for development in a number of conditions including cancer models, cardiac ischemia, seizures, depression, and anxiety. PK-11195 has been studied extensively in vitro and in animal models. In phase I clinical trials no anti-inchemic effects were found after drug administration. A tritium [3H] labeled and a C-11 labeled version of PK-11195 are both used diagnostically as PET imaging compounds.

N-oleoyldopamine is an endogenous lipid compound found in the mammalian brain. It has been found to be a capsaicin receptor (TRPV1) agonist. Activation of the capsaicin receptor induces glutamate release and paraventricular nucleus postsynaptic firing. N-oleoyldopamine has been reported to induce the influx of calcium in TRPV1-transfected HEK293 human embryonic kidney cells.

ATC-0065 is an oral antagonist of melanin concentrating hormone receptor 1. In preclinical testing ATC-0065 demonstrated anxiolytic and antidepressant activity.

ATC-0175 is a potent antagonist with a high affinity for MCH1R and additional affinities for 5-HT1A and 5-HT2B receptors. The receptor binding and the functional assay (MCH-induced increase in [Ca2+]i) indicated that ATC0175 is a noncompetitive antagonist at MCH1Rs. ATC-0175 exhibited anxiolytic effects in numerous animal models of anxiety including the elevated plus-maze test, social interaction test, stress-induced hyperthermia and maternal separation-induced vocalization. ATC-0175 also exhibited antidepressant effects in the forced swimming test. ATC-0175 increased swimming performance without altering climbing behavior, as observed with selective serotonin reuptake inhibitors. ATC0175 has adequate ADME profile (reasonable oral bioavailability and brain penetration) and potent oral activity in animal models. In contrast, ATC-0175 did not affect spontaneous locomotor activity, hexobarbital-induced sleeping time and did not impair rotarod performance. Thus, ATC-0175 may be devoid of unwanted central nervous system side effects, which are sometimes observed with current medications. ATC-0175 has the potential to be effective in the treatment of patients with depression and/or anxiety disorders.

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-841720, a novel, potent and non-competitive mGluR1 antagonist in models of pain and of motor and cognitive function, is being under development by Merz Pharmaceuticals GmbH. It is a selective non-competitive mGlu1 receptor antagonist (IC50: 10 nM); showing 34-fold selectivity over mGluR5 and no significant activity at other mGluR receptors, neurotransmitter receptors, ion channels, and transporters. A-841720 demonstrated full efficacy in various in vivo animal pain models.

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.

Hecogenin acetate is the acetylated form of Hecogenin, a naturally occurring sapogenin present in the leaves of plants from the Agave genus. It has been found to have antinociceptive activity in mice and has also been investigated as an anti-cancer agent in vitro. Hecogenin appears to exert its anticancer influence by modulating the ERK1/2 signal cascade and activates opioid receptors to influence nocioception.