PSNCBAM-1 is a novel negative allosteric modulator of the cannabinoid CB1 receptor. This molecule is shown to produce acute hypophagia and weight loss in male SD rats, and therefore may represent an alternative approach to the current strategies for the treatment of obesity. PSNCBAM-1 allosteric antagonism may provide viable therapeutic alternatives to orthosteric CB1 antagonists/inverse agonists in the treatment of CNS disease. No adverse or toxic effects were seen after long-term PSNCBAM-1 administration in vivo.

Phillyrin, an active ingredient found in many medicinal plants and certain functional foods, elicits anti-obesity and anti-inflammatory properties in vivo. Phillyrin is one of the main chemical constituents of Forsythia suspensa (Thunb.), which has shown to be an important traditional Chinese medicine. Phillyrin, has being shown to possess various bioactivities, including anti-inflammatory, anti-oxidant, and antiviral activities. It has being reported that Phillyrin attenuates high glucose-induced lipid accumulation in human HepG2 hepatocytes through the activation of LKB1/AMP-activated protein kinase-dependent signalling.

1,9-dideoxyforskolin from Coleus forskohlii (forskolin), a highly oxygenated labdane diterpenoid is an activator of adenylate cyclase. An extract of the plant Coleus forskohlii has been used for centuries in Ayurvedic medicine to treat various diseases such as hypothyroidism, heart disease, and respiratory disorders. Preliminary studies have shown that forskolin can increase fat metabolism thus reduce fat accumulation in both animals and humans. Coleus forskohlii extract and forskolin extract were investigated for treatment obesity and in preventing asthma attacks in patients with mild persistent or moderate persistent asthma. Extracted from the aerial parts of Coleus forskohlii forskolin was also found to be active against HIV(NL4-3). Forskolin can be synthesized in 12 steps (12% overall yield) from ptychantin A, which has been isolated from liverwort Ptychanthus striatus and is a widely used as a biochemical tool. It activates adenyl cyclase, thereby increasing intracellular concentration of cAMP and thus activating the protein kinase A (PKA) signal transduction pathway. PKA-dependent and -independent effects of forskolin on the expression of drug-metabolizing enzymes in liver suggested that herbal therapy with C. forskohlii extract should be approached cautiously due to the potential for herb-drug interactions in patients on combination therapy.

GW-4064 is a synthetic small molecule selective agonist of the orphan nuclear receptor FXR developed by GlaxoSmithKline. GW-4064-mediated FXR activation ameliorates diet-induced obesity, suppresses hepatic lipid accumulation, and maintains glucose and lipid homeostasis in C57BL/6 mice. GW-4064-treated tumors exhibited decreased levels of leptin-regulated proteins along with a strong staining intensity for SOCS3. Thus, FXR ligand GW-4064 might represent an emerging potential anti-cancer therapy able to block the tumor supportive role of activated fibroblasts within the breast microenvironment.

Epicatechin-5-Sulfate is a metabolite of epicatechin. It is patented for inclusion in food formulations intended for weight loss, and treatment of diabetes.

Piceatannol (3,3′,4,5′-tetrahydroxy-trans-stilbene; PIC) is a naturally occurring stilbene present in diverse plant sources. Piceatannol is a hydroxylated analog of resveratrol and produced from resveratrol by microsomal cytochrome P450 1A11/2 and 1B1 activities. Like resveratrol, Piceatannol has a broad spectrum of health beneficial effects, many of which are attributable to its antioxidative and anti-inflammatory activities. Piceatannol exerts anticarcinogenic effects by targeting specific proteins involved in regulating cancer cell proliferation, survival/death, invasion, metastasis, angiogenesis, etc. in the tumor microenvironment. Piceatannol also has other health promoting and disease preventing functions, such as anti-obese, antidiabetic, neuroprotective, cardioprotective, anti-allergic, anti-aging properties. A comprehensive review of PIC concludes that the compound has the health promoting and disease preventive potential. However, low water-solubility and bioavailability of PIC limit its pharmaceutical application and also use in functional foods. In this context, it is noticeable that beta-cyclodextrin was found to improve the bioavailability, the solubility and the stability of Piceatannol.

CP-640186 is a potent inhibitor of mammalian ACCs and can reduce body weight and improve insulin sensitivity in test animals. CP-640186 has recently been shown to be a potent inhibitor of isoforms of mammalian ACCs with IC50 values of about 55 nM. This is currently the only reported potent inhibitor of mammalian ACCs. In cell cultures as well as in animal models, CP-640186 can reduce tissue malonyl-CoA levels, inhibit fatty acid biosynthesis, and stimulate fatty acid oxidation. Most importantly, CP-640186 can reduce body fat mass and body weight, and improve insulin sensitivity, validating ACCs as targets for antiobesity and antidiabetes drugs.CP-640186 potently inhibited HepG2 cell fatty acid and TG synthesis. CP-640186 also stimulated fatty acid oxidation in C2C12 cells (ACC2) and in rat epitrochlearis muscle strips with EC50s of 57 nm and 1.3 uM. In rats, CP-640186 lowered hepatic, soleus muscle, quadriceps muscle, and cardiac muscle malonyl-CoA with ED50s of 55, 6, 15, and 8 mg/kg. Consequently, CP-640186 inhibited fatty acid synthesis in rats, CD1 mice, and ob/ob mice with ED50s of 13, 11, and 4 mg/kg, and stimulated rat whole body fatty acid oxidation with an ED50 of approximately 30 mg/kg.

Hypaphorine is the alkaloid isolated from the seeds of Brazilian medicinal plant Erythrina spp. This compound was investigated for sleep-promoting effects in mice, and the results showed that it significantly increased non-rapid eye movement (NREM) sleep time during the first hour after its administration. Hypaphorine prevented the differentiation of 3T3-L1 preadipocytes into adipocytes by down-regulating hormone-stimulated protein expression of peroxisome proliferator activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (C/EBPα), and their downstream targets, sterol regulatory element binding protein 1 c (SREBP1c) and fatty acid synthase (FAS). Hypaphorine may exert anti-inflammatory actions through the regulation of TLR4 and PPAR-γ dependent on PI3K/Akt/mTOR signal pathways. It is considered as a therapeutic agent that can potentially relieve or ameliorate endothelial inflammation-associated diseases. Hypaphorine was also a key component of Vaccaria segetalis. Vaccaria hypaphorine might be considered as a potential therapeutic agent for treating osteoclast-based bone loss.

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.

BVT-2733 is an inhibitor of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) that exhibits anti-diabetic, anti-inflammatory, and anti-osteoporotic properties. BVT-2733 decreases blood glucose and serum insulin levels in animal models of hyperglycemia. BVT-2733 also attenuates arthritis severity, decreases pro-inflammatory cytokine production, and suppresses synovial inflammation. In other animal models, this compound prevents 11βHSD-induced osteogenic differentiation and suppression of osteogenesis. BVT-2733 had reasonable mouse potency (IC50 = 96nM) but was only weakly active against the human isoform (IC50 = 3341 nM). This combined with moderate mouse pharmacokinetics (F = 21%) made it a suitable in vivo tool with which to explore the potential of 11β-HSD1 as a mechanism for the treatment of type II diabetes. In KKAy mice, oral dosing twice daily (25, 50, 100 mg/kg) of BVT-2733 lowered blood glucose levels in a dose-dependent manner.