Evodiamine, a naturally occurring indole alkaloid, is one of the main bioactive ingredients of Evodia Rutaecara, the dried unripe fruit of which is also known as Wu zhu yu (Wu Zhu Yu, interchangeably) or Evodia Fruit. Evodia Fruit used in Traditional Chinese Medicine for the purposes of warmth, intestinal comfort (specifically; to alleviate abdominal pain, acid regurgitation, nausea and diarrhea), dysmenorrheal, and fighting inflammation and infections. With respect to the pharmacological actions of evodiamine, more attention has been paid to beneficial effects in insults involving cancer, obesity, nociception, inflammation, cardiovascular diseases, Alzheimer's disease, infectious diseases and thermo-regulative effects. Evodiamine has evolved a superior ability to bind various proteins including TRPV1, the aryl hydrocarbon receptor (AhR), and topoisomerases I and II. There are currently no human studies on evodia rutaecarpa berries or evodiamine.

Verticine is a steroidal alkaloid compound extracted from the Fritillaria species of medicinal plants. Verticine was not only able to block the Nav1.7 ion channel but also preferably inhibited the Kv1.3 ion channel. It inhibits the production of inflammatory cytokines induced by LPS through blocking MAPKs and NF-κB signaling pathways. Verticine inhibited the hERG peak tail currents in a concentration dependent manner. Verticine exhibits anti-inflammatory, antitussive, antihypertensive and pain suppression properties.

JTC 801 was developed by Japan Tobacco as a novel opioid receptor-like1 (ORL(1)) receptor antagonist. It was found, that JTC-801 completely antagonized the suppression of nociceptin on the forskolin-induced accumulation of cyclic AMP using ORL(1) receptor expressing HeLa cells in vitro. JTC 801 produced analgesic effects and was studied in phase II of a clinical trial for the treatment of neuropathic, cancer and postoperative pain. Nevertheless, that studies were discontinued.

ELN-441958 was developed by Elan pharmaceutical as a novel small molecule bradykinin B1 receptor antagonist against pain.

AMG-9810, is a TRPV1 (vanilloid receptor 1) antagonist which blocks all known modes of TRPV1 activation, including heat, proton, and endogenous ligand activation. TRPV1 is a membrane-bound cation channel in peripheral sensory neurons. Inhibition of this receptor has been noted to cause anti-inflammatory effects. In murine dorsal root ganglion primary neuron studies, this compound has been shown to block capsaicin-evoked depolarization and calcitonin gene-related peptide release. Screening of AMG 9810 against a panel of G protein-coupled receptors and ion channels indicated selectivity toward TRPV1. In vivo, AMG-9810 is effective at preventing capsaicin-induced eye wiping in a dose-dependent manner, and it reverses thermal and mechanical hyperalgesia in a model of inflammatory pain induced by intraplantar injection of complete Freund's adjuvant. AMG-9810 is the first cinnamide TRPV1 antagonist reported to block capsaicin-induced eye wiping behavior and reverse hyperalgesia in an animal model of inflammatory pain.

JNJ-17203212 is an TRPV1 receptor antagonist. The drug exerts potent antinociceptive and antitussive actions. JNJ-17203212 is developing by Johnson & Johnson for the treatment of pain and cough. No development reported.

1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea (A-425619), a novel, potent, and selective transient receptor potential type V1 (TRPV1) antagonist, attenuates pain associated with inflammation and tissue injury in rats. A-425619 was found to potently block capsaicin-evoked increases in intracellular calcium concentrations in HEK293 cells expressing recombinant human TRPV1 receptors (IC50 = 5 nM). A-425619 showed similar potency (IC50 = 3-4 nM) to block TRPV1 receptor activation by anandamide and N-arachidonoyl-dopamine. Electrophysiological experiments showed that A-425619 also potently blocked the activation of native TRPV1 channels in rat dorsal root ganglion neurons (IC50 = 9 nM). In vivo, A-425619 dose dependently reduced capsaicin-induced mechanical hyperalgesia (ED50 = 45 umol/kg p.o.). A-425619 was also effective in models of inflammatory pain and postoperative pain. A-425619 potently reduced complete Freund's adjuvant-induced chronic inflammatory pain after oral administration (ED50 = 40 umol/kg p.o.) and was also effective after either i.t. administration or local injection into the inflamed paw. Furthermore, A-425619 maintained efficacy in the postoperative pain model after twice daily dosing p.o. for 5 days. A-425619 also showed partial efficacy in models of neuropathic pain. A-425619 did not alter motor performance at the highest dose tested (300 micromol/kg p.o.). A-425619, a potent and selective antagonist of TRPV1 receptors, effectively relieves acute and chronic inflammatory pain and postoperative pain.

JNJ-1661010 is a potent and selective is a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. FAAH is a membrane bound serine hydrolase primarily responsible for the breakdown of the endogenous cannabinoid anandamide in the CNS. Increasing the amount of anandamide, which has analgesics properties, may be efficacious in the treatment of pain. According to the experimental data JNJ-1661010 may be useful clinically as broad-spectrum analgesics. Johnson & Johnson is developing JNJ-1661010 for the treatment of neuropathic pain. Preclinical development is being conducted in the US. In addition recent data demonstrated that JNJ-1661010 could be useful in the treatment of arthritis and parkinson's disease. JNJ-1661010 inhibits myometrial contractility, without un-specific relaxing effects on the smooth muscle.

LY235959 is the active isomer of the 6-substituted decahydroisoquinoline-3-carboxylic acid, LY274614. Both LY274614 and LY235959 have demonstrated potent NMDA receptor antagonist activity both in vivo and in-vitro. LY235959 has been shown to attenuate and reverse morphine tolerance as well as, attenuate opioid withdrawal and block c-fos mRNA induction in limbic areas. The attenuation of morphine tolerance occurs through the interaction of LY235959 with the NMDA receptor and not by producing opiate receptor changes. LY235959 is able to block NMDA receptor-induced hyperalgesia, as well as formalin-induced inflammatory pain, in rats. These antinociceptive effects of LY235959 were obtained at doses that did not produce motor impairment. LY235959 does not block the hyperalgesia produced by kainic acid (a non-NMDA glutamate receptor agonist) providing evidence of its selectivity for the NMDA receptor.

Friedelin is a natural compound with promising proprieties. On its own or with chemical modification it is possible to introduce relevant biological activities, e.g. anti-cancer, anti-aging and agrochemical. Its availability in significant amounts has been a major drawback on its regular use and in the pursuit of different applications. Cork and cork-derived materials (e.g. black condensate) are the most relevant sources of Friedelin in nature (up to 10% in concentration). Friedelin has being shown to possess marked antioxidant and liver protective effects. Friedelin has also being demonstrated to possess potent anti-inflammatory, analgesic and antipyretic activities.