CP-868388 is a potent PPAR-alpha agonist The orally administered CP-868388 is well tolerated. It has been very useful in acute preclinical models for treating dyslipidemia.

2,5-Dimethoxy-4-iodoamphetamine (4-iodo-2,5-dimethoxyphenylisopropylamine or DOI), a psychedelic drug and hallucinogen has high affinity and is a potent agonist for each of the 5-HT2 receptor subtypes: 5-HT2A, 5-HT2B, and 5-HT2C. DOI's effects have been compared to LSD. DOI has a stereo center and R-(−)-DOI is the more active stereoisomer. It was shown, that R-(−)-DOI via 5-HT2A receptor could inhibit a variety of TNF-alpha-mediated proinflammatory markers, including intracellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), and interleukin (IL)-6 gene expression. It is known, that TNF-alpha-mediated inflammatory pathways have been strongly implicated in a number of diseases, including atherosclerosis, rheumatoid arthritis, psoriasis, type II diabetes, depression, schizophrenia, and Alzheimer's disease. Thus, because (R)-DOI can significantly inhibit the effects of TNF-alpha many hours after the administration of TNF-alpha, potential therapies could be aimed not only at preventing inflammation but at also treating the inflammatory injury that has already occurred or is ongoing.

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.

HU-210 is a synthetic cannabinoid. HU-210 is a highly potent cannabinoid receptor agonist. Also, it displays agonist activity at GPR55. HU-210 administration in adult rats results in a dose-dependent inhibition of plasma growth hormone, follicle stimulating hormone, and luteinizing hormone; modifications of plasma adrenocorticotropic hormone (ACTH) and corticosterone levels reveal a dose-dependent action on the pituitary-adrenal axis after acute exposure. HU-210 block beta-amyloid peptide-induced activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and tumor necrosis factor-alpha release; these effects are independent of the antioxidant action of cannabinoid compounds and are also exerted by a CB2-selective agonist. HU-210 induced a spatial deficit in the water maze in learning a reference memory task in numerous parameters together with alterations in hippocampal firing patterns of single principal neurons.

Catalposide is a compound isolated from irinoid-producing plant Catalpa ovata. Catalposide has been shown to possess anti-microbial, anti-tumoral, and anti-inflammatory properties. was found to inhibit the productions of tumor necrosis factor-alpha (TNF- alpha), interleukin-1beta, and interleukin-6 (IL-6), and the activation of nuclear factor kB (NF-kB) in RAW 264.7 macrophages activated with lipopolysaccharide (LPS).

AC260584 (4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one) is a selective muscarinic M1 receptor agonist. The muscarinic M1 receptor agonist property of AC260584 contributes to its enhancement of cortical acetylcholine and dopamine efflux. In animal studies AC-260584 has a behavioral profile consistent with antipsychotic-like efficacy with the potential to improve cognitive performance and shows reduced liability for extrapyramidal symptoms.

Polygodial is a sesquiterpene dialdehyde isolated from the leaves of certain peppers and related plants, that exhibits anti-inflammatory, antiallergic, antinociceptive, anticancer, antifungal and antimicrobial activities. Polygodial’s primary antifungal action is as a nonionic surfactant, disrupting the lipid-protein interface of integral proteins nonspecifically, denaturing their functional conformation. It is also likely that Polygodial permeates by passive diffusion across the plasma membrane, and once inside the cells may react with a variety of intracellular compounds. Polygodial is a component of the “hot taste” in peppery spices of traditional Japanese cuisine.

(+)-3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP or preclamor, (R)) is an agonist of the sigma receptors and also acts as a dopamine receptor agonist with autoreceptor as well as postsynaptic receptor stimulatory properties. In vivo experiments have shown, that preclamor, (R) inhibited DOPA accumulation in the striatum, nucleus accumbens, and medial prefrontal cortex.

SB-206606 (better known as BRL-37344) was developed by Beecham Pharmaceuticals and is currently licensable from GlaxoSmithKline. SB-206606 is an agonist for the Beta-3 adrenergic receptor with an EC 50 value of 17 nM (human B3AR expressed in CHO cells). SB-206606 was in pre-clinical development as a potential treatment of Diabetes Mellitus, although such efforts have been discontinued. Recently it has also garnered some interest as a potential treatment for alcoholism.