Transient receptor potential melastatin 3 (TRPM3) is a calciumpermeable nonselective cation channel that is expressed in a subset of dorsal root (DRG) and trigeminal ganglia sensory neurons. TRPM3 can be activated by the neurosteroid pregnenolone sulfate (PregS) and heat. TRPM3 2/2 mice display an impaired sensation of noxious heat and thermal hyperalgesia. We have previously shown that TRPM3 is blocked by the citrus fruit flavanones hesperetin, naringenin, and eriodictyol as well as by ononetin, a deoxybenzoin from Ononis spinosa. To further improve the tolerability, potency, and selectivity of TRPM3 blockers, we conducted a hit optimization procedure by rescreening a focused library that was composed of chemically related compounds. Within newly identified TRPM3 blockers, isosakuranetin and liquiritigenin displayed favorable properties with respect to their inhibitory potency and a selective mode of action. Isosakuranetin, a flavanone whose glycoside is contained in blood oranges and grapefruits, displayed an IC 50 of 50 nM and is to our knowledge the most potent inhibitor of TRPM3 identified so far. Both compounds exhibited a marked specificity for TRPM3 compared with other sensory TRP channels, and blocked PregS-induced intracellular free Ca 21 concentration signals and ionic currents in freshly isolated DRG neurons. Furthermore, isosakuranetin and previously identified hesperetin significantly reduced the sensitivity of mice to noxious heat and PregS-induced chemical pain. Because the physiologic functions of TRPM3 channels are still poorly defined, the development and validation of potent and selective blockers is expected to contribute to clarifying the role of TRPM3 in vivo.

Bariatric surgery remains the single most effective long-term treatment modality for morbid obesity, achieved mainly by lowering caloric intake through as yet ill-defined mechanisms. Here we show in rats that Roux-en-Y gastric bypass (RYGB)-like rerouting of ingested fat mobilizes lower small intestine production of the fat-satiety molecule oleoylethanolamide (OEA). This was associated with vagus nerve-driven increases in dorsal striatal dopamine release. We also demonstrate that RYGB upregulates striatal dopamine 1 receptor (D1R) expression specifically under high-fat diet feeding conditions. Mechanistically, interfering with local OEA, vagal, and dorsal striatal D1R signaling negated the beneficial effects of RYGB on fat intake and preferences. These findings delineate a molecular/systems pathway through which bariatric surgery improves feeding behavior and may aid in the development of novel weight loss strategies that similarly modify brain reward circuits compromised in obesity.

R(+)-alpha-lipoic acid is a natural occurring compound that acts as an essential cofactor for certain dehydrogenase complexes. The redox couple alpha-lipoic acid/dihydrolipoic acid possesses potent antioxidant activity. Exogenous racemic alpha-lipoic acid orally administered for the symptomatic treatment of diabetic polyneuropathy is readily and nearly completely absorbed, with a limited absolute bioavailability of about 30% caused by high hepatic extraction. Although the pharmacokinetics of the parent drug have been well characterized in humans, relatively little is known regarding the excretion of alpha-lipoic acid and the pharmacokinetics of any metabolites in humans. In the present study, plasma concentration-time courses, urinary excreted amounts, and pharmacokinetic parameters of alpha-lipoic acid metabolites were evaluated in 9 healthy volunteers after multiple once-daily oral administration of 600 mg racemic alpha-lipoic acid. The primary metabolic pathways of alpha-lipoic acid in man, S-methylation and beta-oxidation, were quantitatively confirmed by an HPLC-electrochemical assay newly established prior to the beginning of this study. Major circulating metabolites were the S-methylated beta-oxidation products 4,6-bismethylthio-hexanoic acid and 2,4-bismethylthio-butanoic acid, whereas its conjugated forms accounted for the major portion excreted in urine. There was no statistically significant difference in the pharmacokinetic parameters Cmax, AUC, and tmax between day 1 and day 4. Despite the prolonged half-lives of the major metabolites compared to the parent drug, no evidence of accumulation was found. Mean values of 12.4% of the administered dose were recovered in the urine after 24 hours as the sum of alpha-lipoic acid and its metabolites. The results of the present study revealed that urinary excretion of alpha-lipoic acid and five of its main metabolites does not play a significant role in the elimination of alpha-lipoic acid. Therefore, biliary excretion, further electrochemically inactive degradation products, and complete utilization of alpha-lipoic acid as a primary substrate in the endogenous metabolism should be considered.

The results indicate that CYP1A2-catalyzed N-dealkylation and gamma hydroxylation are the major routes for BM phase I metabolism producing two metabolites less or similarly toxic than the parent compound. In contrast to the metabolic pathways of the structurally related chlorambucil, no beta-oxidation of the butanoic acid side chain leading to enhanced toxicity was detected for BM.

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