新規選択的ボンベシンサブタイプ3受容体アゴニストは脳-肝リズムを変化させて抗肥満作用を示す。

Abstract

Bombesin receptor subtype 3 (BRS-3) is an orphan G protein-coupled receptor. Based on the obese phenotype of male BRS-3-deficient mice, BRS-3 has been considered an attractive target for obesity treatment. Here, we developed a novel selective BRS-3 agonist (compound-A) and evaluated its antiobesity effects. Compound-A showed anorectic effects and enhanced energy expenditure in dietinduced-obese (DIO)-F344 rats. Moreover, repeated oral administration of compound-A for 7 days resulted in a significant body weight reduction in DIO-F344 rats. To investigate the underlying mechanisms of BRS-3 agonist effects, we focused on the suprachiasmatic nucleus (SCN), the main control center of circadian rhythms in the hypothalamus, also regulating sympathetic nervous system. Compound-A significantly increased the messenger RNA expression of Brs-3, c-fos, and circadian rhythm genes in SCN of DIO-F344 rats. On this basis, energy expenditure enhancement by compound-A may be due to a circadian rhythm change in central and peripheral tissues, enhancement of peripheral lipid metabolism, and stimulation of the sympathetic nervous system. According to these results, BRS-3 agonist might be a good option for obesity treatment with circadian rhythm change and increase of energy expenditure.

Bombesin receptor subtype‐3‐expressing neurons regulate energy homeostasis through a novel neuronal pathway in the hypothalamus

“…Compound‐A is an active conformer (tR2(IC)) of BRS‐3 agonist as previously reported (Nio et al., ). Compound‐A had agonistic activity with an EC 50 value of 100 nM (95% confidence interval: 59–172 nM) as per the aequorin assay (Ca 2+ ) against rat BRS‐3, but did not show agonistic action at 10 uM to human GRPR and NMBR.…”

“…The pharmacokinetic profile of compound‐A (1 mg/kg, po) in SD rats was determined and the maximum plasma concentration (Cmax), time at which the Cmax was observed (Tmax), and bioavailability (BA) were found to be 69.1 ng/ml, 0.5 hr, and 21.7%, respectively. Our previous study revealed that the compound‐C can pass the blood–brain barrier, suggesting that compound‐A could pass the blood–brain barrier (Nio et al., ).…”

“…Compound‐A had agonistic activity with an EC 50 value of 100 nM (95% confidence interval: 59–172 nM) as per the aequorin assay (Ca 2+ ) against rat BRS‐3, but did not show agonistic action at 10 uM to human GRPR and NMBR. Compound‐C is the racemate of compound‐A (Nio et al., ) and had agonistic activity with an EC 50 value of 130 nM against rat BRS‐3 (Ca 2+ ). The pharmacokinetic profile of compound‐A (1 mg/kg, po) in SD rats was determined and the maximum plasma concentration (Cmax), time at which the Cmax was observed (Tmax), and bioavailability (BA) were found to be 69.1 ng/ml, 0.5 hr, and 21.7%, respectively.…”

“…Compound‐A (active conformer (tR2(IC)), 6‐benzyl‐ N ‐ tert ‐butyl‐9‐methoxy‐7‐oxo‐6,7‐dihydro‐ 5H ‐dibenzo[c,e]azepine‐5‐carboxamide) and compound‐C (racemate) were synthesized at Takeda Pharmaceutical Company Limited as previously reported (Nio et al., ). Sibutramine and CL316,243 were purchased from Wako Pure Chemical (Osaka, Japan) and Tocris Bioscience (Bristol, UK), respectively.…”

“…Recently, we reported a novel selective nonpeptide BRS‐3 agonist, compound‐A (Nio et al., ). Compound‐A shows clear anorectic effects and enhanced energy expenditure in rats, suggesting that this compound is an useful tool compound to assess the function of BRS‐3 neurons.…”