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.

PF-3845 is a selective covalent inhibitor of fatty acid amide hydrolase. It results in increased levels of anandamide and results in cannabinoid receptor-based effects. PF-3845 demonstrated cannabinoid receptor-dependent antinociceptive effects in models of inflammatory and neuropathic pain. In mouse model PF-3845 attenuated withdrawal from morphine dependence. PF3845 reversed traumatic brain injury (TBI)-induced impairments in fine motor movement, hippocampus dependent working memory and anxiety-like behavior in a tramatic brain injury model.

3-(2-Carboxypiperazin-4-yl)Propyl-1-Phosphonic acid (also known as CPP) is neuro active amino acid and antagonist of the N-methyl-D-aspartate receptor (NMDA). It has been studied in rat models for memory, learning, and pain. Although it did show some efficacy in reducing pain it also appears to significantly impair working memory.

Dihydroisocodeine is an opioid derivative. Dihydroisocodeine is much less toxic for rabbits than codeine, and in these and other animals its convulsant action is less marked. The minimum analgesic dose for cats is considerably less than for codeine. In the 1930s it was clinically investigated for cough relief, where it has no demonstrable clinical superiority over standard codeine in the usual therapeutic dosage.

NS1738 (1-(5-chloro-2-hydroxy-phenyl)-3-(2-chloro- 5-trifluoromethyl-phenyl)-urea) is a positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor (nAChR). NS1738 is capable of producing cognitive enhancement in vivo. NS1738 significantly reduced thermal hyperalgesia in mice.

BAY-59-3074 is a novel, selective cannabinoid CB(1)/CB(2) receptor ligand (K(i) = 55.4, 48.3, and 45.5 nM at rat and human cannabinoid CB(1) and human CB(2) receptors, respectively), with partial agonist properties at these receptors in guanosine 5-[gamma(35)S]-thiophosphate triethyl-ammonium salt ([(35)S]GTPgammaS) binding assays. It displays anti-hyperalgesic and antiallodynic properties in rat models of chronic neuropathic and inflammatory pain. BAY-59-3074 may offer a valuable therapeutic approach to treat diverse chronic pain conditions.

(R)-Etifoxine is an isomer, chemically isolated from Etifoxine (Stresam), an approved racemic drug (off patent) prescribed in Europe. (R)-Etifoxine was developed by Xytis Inc for treatment pain, mental disease, and central nervous system disorders. However future development has been discontinued.

PD 173212 is a potent, selective N-type voltage-gated Ca2+ channel blocker (IC50 = 36 nM), it possesses selectivity for non L-type Ca ÷2 channels versus neuronal Na ÷, K ÷, and L-type Ca ÷2 channels. PD 173212 demonstrated potent in vitro activity in the IMR-32 assay as well as in electrophysiology, and it was efficacious in the audiogenic seizure mouse model.

Rosmanol is a natural polyphenol from the herb rosemary (Rosmarinus officinalis L.) with high antioxidant activity. Rosmanol markedly inhibited LPS-stimulated iNOS and COX-2 protein and gene expression, as well as the downstream products, NO and PGE2 in RAW 264.7 cells. Treatment with Rosmanol also reduced translocation of the nuclear factor-κB (NF-κB) subunits by prevention of the degradation and phosphorylation of inhibitor κB (IκB). Rosmanol exerted significant antinociceptive effects in both hot plate and tail immersion tests at the dose level of 10-100 mg/kg. The cellular and neural mechanisms underlying pain responses elicited involve interplay of a number of neurotransmitters and ion channel, and the central analgesic effects of Rosmanol were not antagonized by the opioid receptor antagonist naloxone. This indicates that the central analgesic effects of Rosmanol may be exerted via one or more of several proposed nonopioid mechanisms such as blockade of voltage-gated Na+ channels, activation of the noradrenergic inhibitory system, enhancement of GABAergic and/or serotonergic systems. The physiological and toxicological properties of this compound have not been evaluated in humans.

L-768242 (GW-405,833) is a potent and selective partial agonist for the cannabinoid CB2 receptor with marked anti-inflammatory and anti-hyperalgesic activity in high doses. L-768242 suppresses pathological pain in preclinical models without unwanted central side effects of CB1 agonists. L-768242 dose-dependently reversed established mechanical allodynia in models of neuropathic (i.e. partial sciatic nerve ligation (PSNL) model) and inflammatory (i.e. complete Freund's adjuvant (CFA) model) pain. Despite substantial penetration to the CNS L-768242 did not produce cannabimimetic deficits below doses of 100 mg/kg i.p. Anti-allodynic efficacy of L-768242 was opioid-independent as systemic administration of naltrexone did not block the anti-hyperalgesic or antinociceptive effects of L-768242. In in vitro studies, L-768242 was reported to behave as a partial agonist at human CB2 receptors and, alternately, a potent inverse agonist at both human and rat CB2 receptors and a weak agonist at rat CB1 receptors. L-768242 was suggested to act as a non-competitive CB1 antagonist as L-768242 non-competitively antagonized CP55,940-induced adenylyl cyclase activity, ERK1/2 phosphorylation, PIP2 signaling and CB1 internalization in vitro in HEK cells transfected with CB1 and showed a complex, time-dependent effect on arrestin recruitment in CHO cells. Anti-allodynic efficacy of L-768242 is CB1-dependent but does not seem to involve engagement of the CB1 receptor’s orthosteric site.