JNJ-31020028 was shown to have high affinity for both human and rodent Y2 receptors. The antagonistic property of JNJ-31020028 for the Y2 receptor was demonstrated via inhibition of PYY-stimulated calcium response in KAN-Ts cells expressing a chimeric G protein. After subcutaneous administration, the Y2 antagonist was found to penetrate into the brain and dose dependently occupy Y2 receptor binding sites, demonstrating that the compound engaged its target in the CNS. JNJ-31020028 (15 mg/kg, s.c.) did reverse the anxiogenic effects of withdrawal from a single bolus dose of alcohol on the elevated plus-maze, confirming the anxiolytic-like properties of Neuropeptide Y2 antagonism. JNJ-31020028 has antidepressant like effects in the olfactory bulbectomized model.

Pseudoyohimbine is an alkaloid isolated from the bark of Corynanthe johimbe and Rauwolfia canescens.

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.

Akuammigine is an oxindole alkaloid. Akuammigine shows antiadrenergic activity and thus reduces heart rate.

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.

LY-367385, a potent and selective antagonist of metabotropic glutamate 1a receptor (mGlu1a), which attenuated infarct size after transient focal cerebral ischemia.