DL-Tetrahydropalmatine (dl-THP), an active component isolated from Corydalis species (a Chinese herbal medicine). dl-THP has inhibitory effects on liver injury induced by carbon tetrachloride in mice. The drug demonstrated anxiolytic and anti-nociceptive effects in animal models. dl-THP may act through inhibition of amygdaloid dopamine release to inhibit an epileptic attack – it is a very effective anti-epileptogenic and anticonvulsant agent. dl-THP has been found to have antihypertensive effects. It acts through the 5-HT2 and/or D2-receptor antagonism in the hypothalamus to induce hypotension and bradycardia in rats.

Isopimaric acid is a widely available tricyclic diterpenoid well represented in the resin of conifers of the genera Pinus, Larix, and Picea. It exhibits interesting biological and pharmaceutical properties such as antimicrobial, antiviral, antiallergenic, and anti‐inflammatory activities. It acts as a large conductance Ca2+activated K+ channel (BK channel) opener. BK channel openers have emerged as potentially useful agents in the therapy of various diseases associated with both the central nervous system and smooth muscle system.

Orphanin FQ (OFQ, Nociceptin) is a recently discovered 17-amino acid neuropeptide that is structurally related to the opioid peptides but does not bind opioid receptors. OFQ selectively binds its own receptor (OFQR), which is also sequentially related to the opioid receptors, yet does not bind opioid ligands. OFQ has been proposed to act as an anti-opioid peptide, but its widespread sites of action in the brain suggest that it may have more general functions. Nociceptin acts as an anxiolytic to attenuate behavioral responses to stress. In vivo experiments have demonstrated that Nociceptin modulates a variety of biological functions ranging from nociception to food intake, from memory processes to cardiovascular and renal functions, from spontaneous locomotor activity to gastrointestinal motility, from anxiety to the control of neurotransmitter release at peripheral and central sites. Nociceptin has being shown to directly inhibit an adaptive immune response, i.e., antibody formation, both in vitro and in vivo.

DBO-83 is a 3,8-diazabicyclo[3.2.1]octane derivative with antinociceptive properties. DBO-83 exhibits high affinity for the α4β2 subtype and is a full agonist at α4β2 and ganglionic receptors but lacks appreciable activity at neuromuscular receptors. DBO-83 exhibits antinociceptive activity in both rat and mouse models of acute and persistent pain. In addition DBO-83 modulates memory functions in rodents.

(S)-AM-1241 is enantiomer of the CB2 modulator, that has most penetrated the literature, has proven an important research tool for investigating CB2-mediated antinociception. (R, S)-AM1241 produces antinociception following local and systemic administration in naive rats. Behavioral, neurochemical, and electrophysiological studies suggest that (R, S)-AM1241 suppresses persistent pain through a CB2-specific mechanism. In cAMP inhibition assays, (R, S)-AM1241 was found to be an agonist at human CB(2), but an inverse agonist in rat and mouse CB(2) receptors. (R)-AM1241 bound with more than 40-fold higher affinity than (S)-AM1241, to all three CB(2) receptors and displayed a functional profile similar to that of the racemate. In contrast, S-AM1241 was an agonist at all three CB(2) receptors. In pain models, S-AM1241 was more efficacious than either R-AM1241 or the racemate. In preclinical studies (R, S)-AM1241, (R)-AM1241, and (S)-AM1241 produced antinociception to thermal, but not mechanical, stimulation of the hind paw in naive rats. Antinociception produced by (R, S)-AM1241 and (S)-AM1241 exhibited an inverted U-shaped dose-response curve. (R)-AM1241 produced greater antinociception than either (S)-AM1241 or (R, S)-AM1241. (R, S)-AM1241, (R)-AM1241, and (S)-AM1241 each produced CB2-mediated antinociception that was blocked by SR144528 but not by rimonabant. Local and systemic naloxone blocked morphine-induced antinociception but did not block antinociceptive effects of (R, S)-AM1241, (R)-AM1241, or (S)-AM1241. The physiological and toxicological properties of (S)-AM-1241 have not been evaluated in humans.

AM-251 is a 123I radioisotope and potent CB1 receptor antagonist derivative of the CB1 cannabinoid receptor inverse agonist SR141716A, presenting a radioprobe for in vivo binding studies at the CB1 receptor with a higher affinity (Ki = 7.49 nM) for CB1 than the parent compound (Ki = 11.5 nM). AM-251 has been employed in competitive binding studies to identify CB1 affinity of different cannabimimetic agonists in vivo. AM-251 is also a potent activator of the GPR55 receptor. Daily injection of AM-251 in obese Zucker rats produced a marked and sustained decrease in daily food intake and body weight and a considerable increase in energy expenditure in comparison with untreated obese Zucker rats. AM-251 administration to obese rats significantly reduced plasma levels of glucose, leptin, AST, ALT, Gamma GT, total bilirubin and LDL cholesterol whereas HDL cholesterol plasma levels increased. AM-251 represents a promising therapeutic strategy for the treatment of obesity and metabolic syndrome.

(R)-AM-1241 is enantiomer of the CB2 modulator, that has most penetrated the literature, has proven an important research tool for investigating CB2-mediated antinociception. (R, S)-AM1241 produces antinociception following local and systemic administration in naive rats. Behavioral, neurochemical, and electrophysiological studies suggest that (R, S)-AM1241 suppresses persistent pain through a CB2-specific mechanism. In cAMP inhibition assays, (R, S)-AM1241 was found to be an agonist at human CB(2), but an inverse agonist in rat and mouse CB(2) receptors. (R)-AM1241 bound with more than 40-fold higher affinity than (S)-AM1241, to all three CB(2) receptors and displayed a functional profile similar to that of the racemate. In contrast, S-AM1241 was an agonist at all three CB(2) receptors. In pain models, S-AM1241 was more efficacious than either R-AM1241 or the racemate. In preclinical studies (R, S)-AM1241, (R)-AM1241, and (S)-AM1241 produced antinociception to thermal, but not mechanical, stimulation of the hind paw in naive rats. Antinociception produced by (R, S)-AM1241 and (S)-AM1241 exhibited an inverted U-shaped dose-response curve. (R)-AM1241 produced greater antinociception than either (S)-AM1241 or (R, S)-AM1241. (R, S)-AM1241, (R)-AM1241, and (S)-AM1241 each produced CB2-mediated antinociception that was blocked by SR144528 but not by rimonabant. Local and systemic naloxone blocked morphine-induced antinociception but did not block antinociceptive effects of (R, S)-AM1241, (R)-AM1241, or (S)-AM1241. The physiological and toxicological properties of (R)-AM-1241 have not been evaluated in humans.

Phenthiazamine was developed by Sekizawa et al. as a centrally acting anesthetic for fish. The time required to reduce the positive ganglionic potential in the sympathetic ganglion by phenthiazamine was prolonged in the presence of higher concentrations of Ca2+. The Ca2+-dependent action potential of guinea-pig ureter was reduced by this compound, whereas it did not affect the Na+-dependent action potential.

BRL-54443 is a 5-HT1E and 5-HT1F receptor agonist with pKi of 8.7 and 9.25, respectively, with a weak binding affinity for 5-HT1A, 5-HT1B, 5-HT1D receptors. BRL-54443 (3-300 ug/paw) significantly reduced formalin-induced flinching in rats, indicating that it could be used as a therapeutic strategy to reduce inflammatory pain..

A-317491 (ABT-202) is a non-nucleotide antagonist of P2X3 and P2X2/3 receptor activation. A-317491 potently blocked recombinant human and rat P2X3 and P2X2/3 receptor-mediated calcium flux (Ki = 22-92 nM) and was highly selective (IC50 >10 uM) over other P2 receptors and other neurotransmitter receptors, ion channels, and enzymes. A-317491 also blocked native P2X3 and P2X2/3 receptors in rat dorsal root ganglion neurons. Blockade of P2X3 containing channels was stereospecific because the R-enantiomer (A-317344) of A-317491 was significantly less active at P2X3 and P2X2/3 receptors. A-317491 dose-dependently (ED50 = 30 umolkg s.c.) reduced complete Freund's adjuvant-induced thermal hyperalgesia in the rat. Studies indicate that the P2X3 receptor is implicated in both neuropathic and inflammatory pain. P2X3 receptor is a promising target for therapeutic intervention in cancer patients for pain management. ABT-202 had been in phase I clinical trials by Abbott and NeuroSearch for the treatment of pain. However, this research has been discontinued.