Regulation of Energy Homeostasis by Bombesin Receptor Subtype-3: Selective Receptor Agonists for the Treatment of Obesity

Guan, Xiao-Ming; Chen, Howard; Dobbelaar, Peter H.; Dong, Yan; Fong, Tung M.; Gagen, Karen; Gorski, Judith N.; He, Shuwen; Howard, Andrew D.; Jian, Tianying; Jiang, Michael; Kan, Yanqing; Kelly, Theresa M.; Kosinski, Jennifer; Lin, Linus S.; Liu, Jian; Marsh, Donald J.; Metzger, Joseph M.; Miller, Randy R.; Nargund, Ravi P.; Palyha, Oksana; Shearman, Lauren P.; Shen, Zhu; Stearns, Ralph A.; Strack, Alison M.; Stribling, Sloan; Tang, Yui S.; Wang, Shengping; White, Alan W.; Yu, Hong; Reitman, Marc L.

doi:10.1016/j.cmet.2009.12.008

Cited by 80 publications

(158 citation statements)

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“…Mice were housed in a temperature-and humidity-controlled environment with a 12:12-h light-dark cycle and with food and water available ad libitum. Food intake was measured as described (12). All animal procedures were performed in compliance with National Institutes of Health guidelines and approved by the Merck Research Laboratories Institutional Animal Care and Use Committee, Rahway, NJ.…”

Section: Compoundsmentioning

confidence: 99%

“…Ϫ/Ϫ , and Lepr db/db mice, suggesting that BRS-3 has a role in energy homeostasis that complements these regulatory pathways (12). BRS-3 agonists are a potential new approach to the treatment of obesity.…”

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confidence: 99%

“…BRS-3 is expressed chiefly in specific brain regions, including the hypothalamus, caudal brainstem, and several midbrain nuclei (12,26,31,37). Despite its name and sequence similarity, BRS-3 has a low affinity for bombesin and its natural, endogenous ligand(s) is unknown (19).…”

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confidence: 99%

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Body temperature as a mouse pharmacodynamic response to bombesin receptor subtype-3 agonists and other potential obesity treatments

Metzger¹,

Gagen²,

Raustad³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Lanza T, Lin LS, Nargund RP, Guan XM, Strack AM, Reitman ML. Body temperature as a mouse pharmacodynamic response to bombesin receptor subtype-3 agonists and other potential obesity treatments. Am J Physiol Endocrinol Metab 299: E816 -E824, 2010. First published August 31, 2010; doi:10.1152/ajpendo.00404.2010.-Treatment of rodents with a bombesin receptor subtype-3 (BRS-3) agonist reduces food intake and increases fasting metabolic rate, causing weight loss with continued treatment. In small mammals, core body temperature (Tb) is regulated in part by nutritional status, with a reduced Tb during fasting. We report that fed Brs3 knockout mice have a lower T b, which is discordant with their nutritional status. Treatment of wild-type mice with a BRS-3 agonist increased Tb, more so when the baseline Tb was reduced such as by fasting or during the inactive phase of the light cycle. With repeated BRS-3 agonist dosing, the Tb increase attenuated despite continued weight loss efficacy. The increase in T b was not prevented by inhibitors of prostaglandin E (PGE) production but was partially reduced by a ␤-adrenergic blocker. These results demonstrate that BRS-3 has a role in body temperature regulation, presumably secondary to its effect on energy metabolism, including effects on sympathetic tone. By making use of this phenomenon, the reversal of the fasting Tb reduction was developed into a sensitive single-dose pharmacodynamic assay for BRS-3 agonism and other antiobesity compounds acting by various mechanisms, including sibutramine, cannabinoid-1, and melanin-concentrating hormone-1 receptor blockers, and melanocortin, ␤3-adrenergic, and cholecystokinin-1 receptor agonists. These drugs increased both the fasted Tb and the fasted, resting metabolic rates. The Tb assay is a robust, information-rich assay that is simpler and has a greater throughput than measuring metabolic rate and is a practical, effective tool for drug discovery. tachyphylaxis; metabolic rate; thermoregulation; fasting; drug discovery MAMMALS ARE HOMEOTHERMS, regulating their core body temperature (T b ) within a narrow range (30). T b impacts all facets of life, ranging from chemical reaction rates to defense against infection. Mammals typically live in environments below their thermoneutral range, so maintenance of T b involves generating and conserving heat. Heat is generated as a byproduct of metabolic processes and via dedicated heat generation ("facultative thermogenesis") that occurs principally in brown adipose tissue, a specialized tissue whose only known function is efficient heat generation (5). Heat is conserved through a variety of mechanisms, including behavioral (nests, huddling, choice of warm environment), anatomic (fur, increased body size), and physiological (vasoconstriction, regulation of energy expenditure) mechanisms (11).Small mammals maintain their T b , despite their increased heat loss to the environment, by burning a significant fraction of their energy intake for warmth. For example, about one-third of the food intake is ...

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Section: Compoundsmentioning

confidence: 99%

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Body temperature as a mouse pharmacodynamic response to bombesin receptor subtype-3 agonists and other potential obesity treatments

Metzger¹,

Gagen²,

Raustad³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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“…Results of in vivo testing with this compound furnished a preclinical proof of concept for the BRS-3 mechanism: Administration of the BRS-3 agonist in established diet-induced obese (eDIO) mice caused a significant reduction of acute food intake and increase in fasting metabolic rate, and these effects were not evident in Brs3 null (KO) mice. 13 Furthermore, subchronic dosing (100 mpk BID, 8 days) led to mechanism-based body weight lowering in eDIO mice, while it had no significant effects in KO mice. 13 Undesirable features of 2 were its poor oral pharmacokinetics in preclinical species and a suboptimal off-target profile that included low micromolar binding to the human inward rectifying potassium ion channel (hERG, IC 50 = 1.2 μM) as well as the diltiazem (DLZ) site of the rabbit calcium ion channel (IC 50 = 0.5 μM).…”

mentioning

confidence: 98%

“…13 Furthermore, subchronic dosing (100 mpk BID, 8 days) led to mechanism-based body weight lowering in eDIO mice, while it had no significant effects in KO mice. 13 Undesirable features of 2 were its poor oral pharmacokinetics in preclinical species and a suboptimal off-target profile that included low micromolar binding to the human inward rectifying potassium ion channel (hERG, IC 50 = 1.2 μM) as well as the diltiazem (DLZ) site of the rabbit calcium ion channel (IC 50 = 0.5 μM).…”

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Discovery of MK-7725, A Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity

Chobanian

Guo

Liu

et al. 2012

ACS Med. Chem. Lett.

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We report the development and characterization of compound 22 (MK-5046), a potent, selective small molecule agonist of BRS-3 (bombesin receptor subtype-3). In pharmacological testing using diet-induced obese mice, compound 22 caused mechanism-based, dose-dependent reductions in food intake and body weight.KEYWORDS MK-5046, bombesin receptor subtype-3 agonist, obesity T he mammalian bombesin G-protein-coupled receptor subfamily 1 comprises three structurally related members, the receptors for neuromedin B (NMBR or BB1), gastrin-releasing peptide (GRPR or BB2), 2 and bombesin receptor subtype-3 (BRS-3 or BB3). 3 BRS-3 is an orphan receptor whose natural ligand is not known and which, despite its name, does not bind bombesin with high affinity. BRS-3 is expressed predominantly in the central nervous system (CNS). Mice lacking functional BRS-3 develop mild obesity and insulin resistance, suggesting a role for the receptor in the regulation of energy homeostasis. 4 In addition, BRS-3 as well as the other mammalian family members are expressed by several human carcinoma cell lines, where they may play a role in growth regulation. 3 Until recently, there have been limited reports of peptide 5 or smallmolecule 6-9 pharmacological tools to further elucidate the role of the receptor and determine its potential as a drug target.Our laboratory has described the lead identification and initial optimization of the first reported series of smallmolecule BRS-3 agonists with efficacy in body weight lowering. [10][11][12] Exploratory medicinal chemistry efforts focused on lead 1. The potency at the human receptor was improved through the incorporation of branched substituents at the 4-position of the imidazole, while systemic and CNS exposure were increased through replacement of the benzoic acid moiety with pyridine. This work eventually led to the identification of 2 (Bag-1), the first key pharmacological tool in our program. Results of in vivo testing with this compound furnished a preclinical proof of concept for the BRS-3 mechanism: Administration of the BRS-3 agonist in established diet-induced obese (eDIO) mice caused a significant reduction of acute food intake and increase in fasting metabolic rate, and these effects were not evident in Brs3 null (KO) mice. 13 Furthermore, subchronic dosing (100 mpk BID, 8 days) led to mechanism-based body weight lowering in eDIO mice, while it had no significant effects in KO mice. 13 Undesirable features of 2 were its poor oral pharmacokinetics in preclinical species and a suboptimal off-target profile that included low micromolar binding to the human inward rectifying potassium ion channel (hERG, IC 50 = 1.2 μM) as well as the diltiazem (DLZ) site of the rabbit calcium ion channel (IC 50 = 0.5 μM).The low unbound exposure of compound 2 was shown to be due primarily to high intrinsic clearance. A bile duct cannulated rat study was performed to examine the fate of the compound after in vivo dosing. For this purpose, a tritium radiolabel was incorporated in the 5-position of th...

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Benzodiazepines

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Privileged Structures in Drug Discovery

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Regulation of Energy Homeostasis by Bombesin Receptor Subtype-3: Selective Receptor Agonists for the Treatment of Obesity

Cited by 80 publications

References 64 publications

Body temperature as a mouse pharmacodynamic response to bombesin receptor subtype-3 agonists and other potential obesity treatments

Body temperature as a mouse pharmacodynamic response to bombesin receptor subtype-3 agonists and other potential obesity treatments

Discovery of MK-7725, A Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity

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