Xiao-Ming Guan

Publications (28)145.99 Total impact

• Article: The design and synthesis of potent, selective benzodiazepine sulfonamide bombesin receptor subtype 3 (BRS-3) agonists with an increased barrier of atropisomerization.

  Harry R Chobanian, Yan Guo, Ping Liu, Thomas J Lanza, Marc Chioda, Linda Chang, Theresa M Kelly, Yanqing Kan, Oksana Palyha, Xiao-Ming Guan, [......], Jasminka Dragovic, Jian G Ning, Wes A Schafer, Christopher J Welch, Xiaoyi Gong, Ying-Duo Gao, Viktor Hornak, Marc L Reitman, Ravi P Nargund, Linus S Lin
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  ABSTRACT: Bombesin receptor subtype 3 (BRS-3) is an orphan G-protein coupled receptor expressed primarily in the hypothalamus which plays a role in the onset of both diabetes and obesity. We report herein our progress made towards identifying a potent, selective bombesin receptor subtype-3 (BRS-3) agonist related to the previously described MK-7725(1) Chobanian et al. (2012) that would prevent atropisomerization through the increase of steric bulk at the C-2 position. This would thereby make clinical development of this class of compounds more cost effective by inhibiting racemization which can occur over long periods of time at room/elevated temperature.
  Bioorganic & medicinal chemistry 03/2012; 20(9):2845-9. · 2.82 Impact Factor
• Article: Discovery of Benzodiazepine Sulfonamide-Based Bombesin Receptor Subtype 3 Agonists and Their Unusual Chirality

  Ping Liu, Thomas J. Lanza, Marc Chioda, Carrie Jones, Harry R. Chobanian, Yan Guo, Linda Chang, Theresa M. Kelly, Yanqing Kan, Oksana Palyha, [......], Christopher J. Welch, Xiaoyi Gong, Ying-Duo Gao, Viktor Hornak, Richard G. Ball, Nancy Tsou, Marc L. Reitman, Matthew J. Wyvratt, Ravi P. Nargund, Linus S. Lin
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  ABSTRACT: We report herein the discovery of benzodiazepine sulfonamide-based bombesin receptor subtype 3 (BRS-3) agonists and their unusual chirality. Starting from a high-throughput screening lead, we prepared a series of BRS-3 agonists with improved potency and pharmacokinetic properties, of which compound 8a caused mechanism-based, dose-dependent food intake reduction and body weight loss after oral dosing in diet-induced obese mice. This effort also led to the discovery of a novel family of chiral molecules originated from the conformationally constrained seven-membered diazepine ring.Keywords: Bombesin receptor subtype 3; BRS-3; agonist; obesity; benzodiazepine sulfonamide; planar chirality; atropisomerism
  10/2011;
• Article: Bombesin receptor subtype-3 (BRS-3) regulates glucose-stimulated insulin secretion in pancreatic islets across multiple species.

  Yue Feng, Xiao-Ming Guan, Jing Li, Joseph M Metzger, Yonghua Zhu, Kirstine Juhl, Bei B Zhang, Nancy A Thornberry, Marc L Reitman, Yun-Ping Zhou
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  ABSTRACT: Bombesin receptor subtype-3 (BRS-3) regulates energy homeostasis, and BRS-3 agonism is being explored as a possible therapy for obesity. Here we study the role of BRS-3 in the regulation of glucose-stimulated insulin secretion (GSIS) and glucose homeostasis. We quantified BRS-3 mRNA in pancreatic islets from multiple species and examined the acute effects of Bag-1, a selective BRS-3 agonist, on GSIS in mouse, rat, and human islets, and on oral glucose tolerance in mice. BRS-3 is highly expressed in human, mouse, rhesus, and dog (but not rat) pancreatic islets and in rodent insulinoma cell lines (INS-1 832/3 and MIN6). Silencing BRS-3 with small interfering RNA or pharmacological blockade with a BRS-3 antagonist, Bantag-1, reduced GSIS in 832/3 cells. In contrast, the BRS-3 agonist (Bag-1) increased GSIS in 832/3 and MIN6 cells. The augmentation of GSIS by Bag-1 was completely blocked by U73122, a phospholipase C inhibitor. Bag-1 also enhanced GSIS in islets isolated from wild-type, but not Brs3 knockout mice. In vivo, Bag-1 reduced glucose levels during oral glucose tolerance test in a BRS-3-dependent manner. BRS-3 agonists also increased GSIS in human islets. These results identify a potential role for BRS-3 in islet physiology, with agonism directly promoting GSIS. Thus, in addition to its potential role in the treatment of obesity, BRS-3 may also regulate blood glucose levels and have a role in the treatment of diabetes mellitus.
  Endocrinology 08/2011; 152(11):4106-15. · 4.46 Impact Factor
• Article: Pyridinesulfonylureas and pyridinesulfonamides as selective bombesin receptor subtype-3 (BRS-3) agonists.

  Michael M-C Lo, Harry R Chobanian, Oksana Palyha, Yanqing Kan, Theresa M Kelly, Xiao-Ming Guan, Marc L Reitman, Jasminka Dragovic, Kathryn A Lyons, Ravi P Nargund, Linus S Lin
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  ABSTRACT: Bombesin receptor subtype-3 (BRS-3) is an orphan G-protein coupled receptor belonging to the subfamily of bombesin-like receptors. BRS-3 is implicated in the development of obesity and diabetes. We report here small-molecule agonists that are based on a 4-(alkylamino)pyridine-3-sulfonamide core. We describe the discovery of 2a, which has mid-nanomolar potency, selectivity for human BRS-3 versus the other bombesin-like receptors, and good bioavailability.
  Bioorganic & medicinal chemistry letters 02/2011; 21(7):2040-3. · 2.65 Impact Factor
• Article: Body temperature as a mouse pharmacodynamic response to bombesin receptor subtype-3 agonists and other potential obesity treatments.

  Joseph M Metzger, Karen Gagen, Kate A Raustad, Liming Yang, Amanda White, Sheng-Ping Wang, Stephanie Craw, Ping Liu, Thomas Lanza, Linus S Lin, Ravi P Nargund, Xiao-Ming Guan, Alison M Strack, Marc L Reitman
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  ABSTRACT: 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 (T(b)) is regulated in part by nutritional status, with a reduced T(b) 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 T(b), more so when the baseline T(b) was reduced such as by fasting or during the inactive phase of the light cycle. With repeated BRS-3 agonist dosing, the T(b) 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 β-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 T(b) 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, β₃-adrenergic, and cholecystokinin-1 receptor agonists. These drugs increased both the fasted T(b) and the fasted, resting metabolic rates. The T(b) 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.
  AJP Endocrinology and Metabolism 11/2010; 299(5):E816-24. · 4.75 Impact Factor
• Article: Discovery of MK-5046, a Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity

  Iyassu K. Sebhat, Christopher Franklin, Michael M.-C. Lo, David Chen, James P. Jewell, Randy Miller, Jianmei Pang, Oksana Palyha, Yanqing Kan, Theresa M. Kelly, [......], Jennifer A. Kosinski, Joseph M. Metzger, Kathryn Lyons, Jasminka Dragovic, Peter R. Guzzo, Alan J. Henderson, Marc L. Reitman, Ravi P. Nargund, Matthew J. Wyvratt, Linus S. Lin
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  ABSTRACT: 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
  10/2010;
• Article: Antiobesity effect of MK-5046, a novel bombesin receptor subtype-3 agonist.

  Xiao-Ming Guan, Joseph M Metzger, Liming Yang, Kate A Raustad, Sheng-Ping Wang, Stephanie K Spann, Jennifer A Kosinski, Hong Yu, Lauren P Shearman, Terry D Faidley, [......], Theresa M Kelly, Iyassu Sebhat, Linus S Lin, Jasminka Dragovic, Kathy A Lyons, Stephanie Craw, Ravi P Nargund, Donald J Marsh, Alison M Strack, Marc L Reitman
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  ABSTRACT: Bombesin receptor subtype-3 (BRS-3) is an orphan G protein-coupled receptor implicated in the regulation of energy homeostasis. Here, we report the biologic effects of a highly optimized BRS-3 agonist, (2S)-1,1,1-trifluoro-2-[4-(1H-pyrazol-1-yl)phenyl]-3-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)propan-2-ol (MK-5046). Single oral doses of MK-5046 inhibited 2-h and overnight food intake and increased fasting metabolic rate in wild-type but not Brs3 knockout mice. Upon dosing for 14 days, MK-5046 at 25 mg · kg(-1) · day(-1) reduced body weight of diet-induced obese mouse by 9% compared with vehicle-dosed controls. In mice, 50% brain receptor occupancy was achieved at a plasma concentration of 0.34 ± 0.23 μM. With chronic dosing, effects on metabolic rate, rather than food intake, seem to be the predominant mechanism for weight reduction by MK-5046. The compound also effectively reduced body weight in rats and caused modest increases in body temperature, heart rate, and blood pressure. These latter effects on temperature, heart rate, and blood pressure were transient in nature and desensitized with continued dosing. MK-5046 is the first BRS-3 agonist with properties suitable for use in larger mammals. In dogs, MK-5046 treatment produced statistically significant and persistent weight loss, which was initially accompanied by increases in body temperature and heart rate that abated with continued dosing. Our results demonstrate antiobesity efficacy for MK-5046 in rodents and dogs and further support BRS-3 agonism as a new approach to the treatment of obesity.
  Journal of Pharmacology and Experimental Therapeutics 10/2010; 336(2):356-64. · 3.83 Impact Factor
• Article: Synthesis and SAR of heterocyclic carboxylic acid isosteres based on 2-biarylethylimidazole as bombesin receptor subtype-3 (BRS-3) agonists for the treatment of obesity.

  Mark Hadden, Allan Goodman, Cheng Guo, Peter R Guzzo, Alan J Henderson, Kevin Pattamana, Megan Ruenz, Bruce J Sargent, Brian Swenson, Larry Yet, [......], Linus S Lin, Constantin Tamvakopoulos, Qianping Peng, Yanqing Kan, Oksana Palyha, Theresa M Kelly, Xiao-Ming Guan, Joseph M Metzger, Marc L Reitman, Ravi P Nargund
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  ABSTRACT: SAR around non-peptidic potent bombesin receptor subtype-3 (BRS-3) agonist lead 2 is presented. Attempts to replace the carboxylic acid with heterocyclic isosteres to improve oral bioavailability and brain penetration are described.
  Bioorganic & medicinal chemistry letters 03/2010; 20(9):2912-5. · 2.65 Impact Factor
• Article: Regulation of energy homeostasis by bombesin receptor subtype-3: selective receptor agonists for the treatment of obesity.

  Xiao-Ming Guan, Howard Chen, Peter H Dobbelaar, Yan Dong, Tung M Fong, Karen Gagen, Judith Gorski, Shuwen He, Andrew D Howard, Tianying Jian, [......], Lauren Shearman, Zhu Shen, Ralph Stearns, Alison M Strack, Sloan Stribling, Yui Sing Tang, Sheng-Ping Wang, Amanda White, Hong Yu, Marc L Reitman
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  ABSTRACT: Bombesin receptor subtype 3 (BRS-3) is a G protein coupled receptor whose natural ligand is unknown. We developed potent, selective agonist (Bag-1, Bag-2) and antagonist (Bantag-1) ligands to explore BRS-3 function. BRS-3-binding sites were identified in the hypothalamus, caudal brainstem, and several midbrain nuclei that harbor monoaminergic cell bodies. Antagonist administration increased food intake and body weight, whereas agonists increased metabolic rate and reduced food intake and body weight. Prolonged high levels of receptor occupancy increased weight loss, suggesting a lack of tachyphylaxis. BRS-3 agonist effectiveness was absent in Brs3(-/Y) (BRS-3 null) mice but was maintained in Npy(-/-)Agrp(-/-), Mc4r(-/-), Cnr1(-/-), and Lepr(db/db) mice. In addition, Brs3(-/Y) mice lost weight upon treatment with either a MC4R agonist or a CB1R inverse agonist. These results demonstrate that BRS-3 has a role in energy homeostasis that complements several well-known pathways and that BRS-3 agonists represent a potential approach to the treatment of obesity.
  Cell metabolism 02/2010; 11(2):101-12. · 17.35 Impact Factor
• Article: Discovery of substituted biphenyl imidazoles as potent, bioavailable bombesin receptor subtype-3 agonists.

  Shuwen He, Peter H Dobbelaar, Jian Liu, Tianying Jian, Iyassu K Sebhat, Linus S Lin, Allan Goodman, Cheng Guo, Peter R Guzzo, Mark Hadden, [......], Scott D Feighner, Carina Tan, Andrew D Howard, Constantin Tamvakopoulos, Qianping Peng, Xiao-Ming Guan, Marc L Reitman, Arthur A Patchett, Matthew J Wyvratt, Ravi P Nargund
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  ABSTRACT: We report SAR studies on a novel non-peptidic bombesin receptor subtype-3 (BRS-3) agonist lead series derived from high-throughput screening hit RY-337. This effort led to the discovery of compound 22e with significantly improved potency at both rodent and human BRS-3.
  Bioorganic & medicinal chemistry letters 02/2010; 20(6):1913-7. · 2.65 Impact Factor
• Article: Synthesis and SAR of derivatives based on 2-biarylethylimidazole as bombesin receptor subtype-3 (BRS-3) agonists for the treatment of obesity.

  Jian Liu, Shuwen He, Tianying Jian, Peter H Dobbelaar, Iyassu K Sebhat, Linus S Lin, Allan Goodman, Cheng Guo, Peter R Guzzo, Mark Hadden, [......], Yanqing Kan, Oksana Palyha, Theresa M Kelly, Xiao-Ming Guan, Andrew D Howard, Donald J Marsh, Joseph M Metzger, Marc L Reitman, Matthew J Wyvratt, Ravi P Nargund
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  ABSTRACT: This Letter describes a series of potent and selective BRS-3 agonists containing a biarylethylimidazole pharmacophore. Extensive SAR studies were carried out with different aryl substitutions. This work led to the identification of a compound 2-{2-[4-(pyridin-2-yl)phenyl]ethyl}-5-(2,2-dimethylbutyl)-1H-imidazole 9 with excellent binding affinity (IC(50)=18 nM, hBRS-3) and functional agonist activity (EC(50)=47 nM, 99% activation). After oral administration, compound 9 had sufficient exposure in diet induced obese mice to demonstrate efficacy in lowering food intake and body weight via BRS-3 activation.
  Bioorganic & medicinal chemistry letters 02/2010; 20(7):2074-7. · 2.65 Impact Factor
• Article: Antiobesity efficacy of a novel cannabinoid-1 receptor inverse agonist, N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), in rodents.

  Tung M Fong, Xiao-Ming Guan, Donald J Marsh, Chun-Pyn Shen, D Sloan Stribling, Kim M Rosko, Julie Lao, Hong Yu, Yue Feng, Jing C Xiao, [......], Ping Liu, Shrenik K Shah, Hongbo Qi, Xinchun Tong, Junying Wang, Suoyu S Xu, Barbara Francis, Alison M Strack, D Euan MacIntyre, Lauren P Shearman
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  ABSTRACT: The cannabinoid-1 receptor (CB1R) has been implicated in the control of energy balance. To explore the pharmacological utility of CB1R inhibition for the treatment of obesity, we evaluated the efficacy of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364) and determined the relationship between efficacy and brain CB1R occupancy in rodents. MK-0364 was shown to be a highly potent CB1R inverse agonist that inhibited the binding and functional activity of various agonists with a binding K(i) of 0.13 nM for the human CB1R in vitro. MK-0364 dose-dependently inhibited food intake and weight gain, with an acute minimum effective dose of 1 mg/kg in diet-induced obese (DIO) rats. CB1R mechanism-based effect was demonstrated for MK-0364 by its lack of efficacy in CB1R-deficient mice. Chronic treatment of DIO rats with MK-0364 dose-dependently led to significant weight loss with a minimum effective dose of 0.3 mg/kg (p.o.), or a plasma C(max) of 87 nM. Weight loss was accompanied by the loss of fat mass. Partial occupancy (30-40%) of brain CB1R by MK-0364 was sufficient to reduce body weight. The magnitude of weight loss was correlated with brain CB1R occupancy. The partial receptor occupancy requirement for efficacy was also consistent with the reduced food intake of the heterozygous mice carrying one disrupted allele of CB1R gene compared with the wild-type mice. These studies demonstrated that MK-0364 is a highly potent and selective CB1R inverse agonist and that it is orally active in rodent models of obesity.
  Journal of Pharmacology and Experimental Therapeutics 07/2007; 321(3):1013-22. · 3.83 Impact Factor
• Article: Design and synthesis of (ant)-agonists that alter appetite and adiposity.

  Lex H T Van der Ploeg, Akio Kanatani, Douglas MacNeil, Tung Ming Fong, Alison Strack, Ravi Nargund, Xiao-Ming Guan
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  ABSTRACT: Over the past decade, hypothalamic circuits have been described that impact energy homeostasis in rodents and humans. Our drug development efforts for the treatment of obesity and the metabolic syndrome have largely focused on selected genetic and/or pharmacologically validated pathways. The translation of these pathways into therapeutics for the treatment of obesity will find its first clinical successes over the coming decade. Initial efforts have focused on gaining a better understanding of the relevance of rodent pharmacological and genetic observations for the development of therapeutics for the treatment of human obesity. We pursue pathways defined by the expression of the ghrelin receptor, melanin-concentrating hormone receptors, melanocortin receptors, cannabinoid receptors and neuropeptide Y1 and Y5 receptors. In this review, we will discuss drug development efforts for the treatment of obesity, focused on selective melanocortin 4 receptor agonists and neuropeptide Y1 and Y5 receptor antagonists. These drug development efforts required an in-depth understanding of cell-based observations which drive the development of compound structure-activity relationships. These include understanding of receptor function in selected cell-based backgrounds and early evaluation and validation of ex vivo observations in appropriate in vivo models. In order to develop selective and safe anti-obesity drugs, diverse approaches are needed to increase the likelihood of clinical success, including: (i) developing a detailed understanding of the predictive value of rodent pathways for treatment of human disease; (ii) knowledge of the exact location of targeted receptor subtypes for the clinical indication under study in order to derive a suitable compound profile; (iii) predictive measures of in vivo and/or ex vivo receptor occupancy required to bring about a desired physiological effect; (iv) predictive parameters that outline that the drug-derived effects are safe and mechanism-based; and (v) the refinement of selected compound classes, aimed at their clinical use.
  Progress in brain research 02/2006; 153:107-18. · 3.04 Impact Factor
• Article: Identification of differential genes in ovarian cancer using representational difference analysis of cDNA.

  Hong Chen, Min Wang, Xin-Yan Wang, Shan Gao, Jun Wang, Xiao-Ming Guan
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  ABSTRACT: To identify differential genes between normal ovarian epithelium tissue and ovarian epithelial cancer using representational difference analysis of cDNA (cDNA-RDA). cDNA-RDA was performed to identify the differentially expressed sequences between cDNAs from cancer tissue and cDNAs from normal ovarian tissue in the same patient who was in the early stage of ovarian serous cystadenocarcinoma. These differentially expressed fragments were cloned and analyzed, then sequenced and compared with known genes. Three differentially expressed cDNA fragments were isolated using cDNA from normal ovarian tissue as tester and cDNA from cancer tissue as driver amplicon by cDNA-RDA. DP III-1 and DP III-2 cDNA clone showed significant homology to the cDNA of alpha actin gene; DP III-3 cDNA clone showed significant homology to the cDNA of transgelin gene. cDNA-RDA can be used to sensitively identify the differentially expressed genes in ovarian serous cystadenocarcinoma. Ovarian serous cystadenocarcinoma involves alteration of multiple genes.
  Chinese Medical Sciences Journal 10/2005; 20(3):185-9.
• Article: Increased melanin concentrating hormone receptor type I in the human hypothalamic infundibular nucleus in cachexia.

  Unga A Unmehopa, Joop J van Heerikhuize, Wenda Spijkstra, John W Woods, Andrew D Howard, Emanuel Zycband, Scott D Feighner, Donna L Hreniuk, Oksana C Palyha, Xiao-Ming Guan, Douglas J Macneil, Lex H T Van der Ploeg, Dick F Swaab
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  ABSTRACT: Melanin-concentrating hormone (MCH) exerts a positive regulation on appetite and binds to the G protein-coupled receptors, MCH1R and MCH2R. In rodents, MCH is produced by neurons in the lateral hypothalamus with projections to various hypothalamic and other brain sites. In the present study, MCH1R was shown, by immunocytochemistry, to be present in the human infundibular nucleus/median eminence, paraventricular nucleus, lateral hypothalamic area, and perifornical area, although in the latter two regions, only a few MCH1R-containing cells were found. In addition, MCH1R staining was found in nerve fibers in the periventricular nucleus, dorsomedial and ventromedial nucleus, suprachiasmatic nucleus, and tuberomammillary nucleus. A significant 1.6 times increase in the number of MCH1R cell body staining was found in the infundibular nucleus in postmortem brain material of cachectic patients, compared with matched controls, supporting a role for this receptor in energy homeostasis in the human.
  Journal of Clinical Endocrinology &amp Metabolism 05/2005; 90(4):2412-9. · 6.50 Impact Factor
• Article: Small-molecule insulin mimetic reduces hyperglycemia and obesity in a nongenetic mouse model of type 2 diabetes.

  Mathias Z Strowski, Zhihua Li, Deborah Szalkowski, Xiaolan Shen, Xiao-Ming Guan, Stefan Jüttner, David E Moller, Bei B Zhang
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  ABSTRACT: Adiposity positively correlates with insulin resistance and is a major risk factor of type 2 diabetes. Administration of exogenous insulin, which acts as an anabolic factor, facilitates adipogenesis. Recently nonpeptidal insulin receptor (IR) activators have been discovered. Here we evaluate the effects of the orally bioavailable small-molecule IR activator (Compound-2) on metabolic abnormalities associated with type 2 diabetes using a nongenetic mouse model in comparison with the effects of a novel non-thiazolidinedione (nTZD) peroxisome proliferator-activated receptor-gamma agonist. Both Compound-2 and nTZD alleviated fasting and postprandial hyperglycemia; accelerated glucose clearance rate; and normalized plasma levels of nonesterified fatty acids, triglycerides, and leptin. Unlike nTZD, which increased body weight gain, and total fat mass, which is a common feature for PPARgamma agonists, Compound-2 prevented body weight gain and hypertrophy of brown, and white adipose tissue depots and the development of hepatic steatosis in the mouse model of type 2 diabetes. The effect of the two compounds on proximal steps in insulin signal transduction pathway was analyzed in tissues. Compound-2 enhanced insulin-stimulated phosphorylation of IR tyrosine and/or Akt in the liver, skeletal muscle, and white adipose tissue, whereas nTZD potentiated the phosphorylation of IR and Akt in the adipose tissue only. In conclusion, small-molecule IR activators have unique features as insulin sensitizers and hold potential utility in the treatment of type 2 diabetes and obesity.
  Endocrinology 12/2004; 145(11):5259-68. · 4.46 Impact Factor
• Article: Exploring the site of anorectic action of peripherally administered synthetic melanocortin peptide MT-II in rats.

  Prashant Trivedi, Michael Jiang, Constantin C Tamvakopoulos, Xiaolan Shen, Hong Yu, Steven Mock, Judy Fenyk-Melody, Lex H T Van der Ploeg, Xiao-Ming Guan
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  ABSTRACT: Melanotan-II (MT-II), a cyclic heptapeptide, is a potent, non-selective melanocortinergic agonist. When administered centrally or systemically, MT-II elicited a profound inhibitory effect on food intake in rodents, presumably via activation of melanocortin-4-receptor (MC4R). In this study, we sought to investigate whether penetration of MT-II and iodo-MT-II into brain parenchyma is required for the anorectic effect following intravenous (IV) administration. Firstly, both MT-II and iodo-MT-II were effective at suppressing appetite in rats following their IV administration. We next surveyed by in vitro autoradiographic studies the distribution of selective (125)I-MT-II binding sites in multiple brain regions including areas important for feeding regulation such as the hypothalamus and caudal brainstem. Upon IV administration of (125)I-MT-II, significant radioactivity could not be detected in various brain regions by autoradiography except for a group of circumventricular organs (CVOs), which are anatomically situated outside the blood-brain barrier (BBB). The most intensely labeled CVOs include the subfornical organ, median eminence, area postrema and choroid plexus, and accumulation of radioactivity at these sites can be blocked by co-injection of excess unlabeled MT-II. Direct measurement of MT-II in the brain and plasma by LC-MS-MS following IV injection confirmed that the degree of MT-II penetration into the brain is negligible. Furthermore, when given peripherally under conditions that suppressed food intake, MT-II did not result in a detectable induction of c-Fos-like immunoreactivity in brain regions where a significantly elevated c-Fos expression was observed following intracerebroventricular injection of this peptide. Our results indicate that MT-II has a very limited brain penetration capability, and its effect on feeding behavior following systemic administration may be mediated by either the brain regions in close proximity to the CVOs or sites outside of the BBB, including CVOs or other peripheral systems.
  Brain Research 08/2003; 977(2):221-30. · 2.73 Impact Factor
• Article: Molecular basis of the pharmacological difference between rat and human bombesin receptor subtype-3 (BRS-3).

  Jie Liu, Zhege J Lao, Jiaping Zhang, M T Schaeffer, Michael M Jiang, Xiao-Ming Guan, Lex H T Van der Ploeg, Tung M Fong
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  ABSTRACT: We cloned the gene and cDNA for rat bombesin receptor subtype-3 (BRS-3) and characterized its mRNA expression pattern and pharmacological properties. Despite the high degree of sequence similarity (80% identical), rat and human BRS-3 differ markedly in their pharmacological properties. Although the natural ligand for BRS-3 is still unknown, a synthetic peptide, dY-Q-W-A-V-(beta-A)-H-F-Nle-amide (dY-bombesin), activates human BRS-3 with an EC(50) of 1.2 nM. In contrast, dY-bombesin had a very poor potency for rat BRS-3 (EC(50) = 2 microM). To understand the molecular basis of this pharmacological difference, we constructed chimeric receptors in which individual extracellular loops of rat BRS-3 were replaced with the corresponding human sequences. Switching the N-terminal region or the second extracellular loop did not significantly change receptor properties. However, switching the third extracellular loop (E3) in the rat BRS-3 resulted in a chimeric receptor (RB3-E3) that behaved almost identically to human BRS-3. RB3-E3 bound dY-bombesin with high affinity (K(i) = 1.2 +/- 0.7 nM), and was activated by dY-bombesin with high potency (EC(50) = 1.8 +/- 0.5 nM). Within the E3 loop, mutation of Y(298)E(299)S(300) to S(298)Q(299)T(300) (RB3-SQT) or of D(306)V(307)P(308) to A(306)M(307)H(308) (RB3-AMH) only partially mimicked the effect of switching the entire E3 loop, and mutation of A(302)E(303) to V(302)D(303) or of V(310)V(311) to I(310)F(311) had little effect on the dY-bombesin potency. These results indicate that the sequence variation in the E3 loop is responsible for the species difference between rat and human BRS-3, and multiple residues in the E3 loop are involved in interactions with the agonist dY-bombesin.
  Biochemistry 08/2002; 41(28):8954-60. · 3.42 Impact Factor
• Article: Melanin-concentrating hormone receptor subtypes 1 and 2: species-specific gene expression.

  Carina P Tan, Hideki Sano, Hisashi Iwaasa, Jie Pan, Andreas W Sailer, Donna L Hreniuk, Scott D Feighner, Oksana C Palyha, Sheng-Shung Pong, David J Figueroa, [......], Michael M Jiang, Hong Yu, Junko Ito, Makoto Ito, Masahiko Ito, Xiao Ming Guan, Douglas J MacNeil, Akio Kanatani, Lex H T Van der Ploeg, Andrew D Howard
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  ABSTRACT: To assess the contribution of potential central nervous system pathways implicated in the control of appetite regulation and energy metabolism, it is essential to first identify appropriate animal models. Melanin-concentrating hormone (MCH), a conserved cyclic neuropeptide implicated in the modulation of food intake, has been shown to bind and activate two G-protein-coupled receptors, called GPR24 and MCHR2, expressed in human brain and other tissues. Here we show that several non-human species (rat, mouse, hamster, guinea pig, and rabbit) do not have functional MCHR2 receptors, or encode a nonfunctional MCHR2 pseudogene while retaining GPR24 expression. We identified three species for further evaluation that express both MCH receptor subtypes. We cloned and functionally characterized dog, ferret, and rhesus GPR24 and MCHR2 in mammalian cells and studied their brain distribution patterns by in situ hybridization. The homology, expression profile, and functional similarity of the receptors in the dog, ferret, and rhesus to that of human support the potential use of these species as preclinical animal models in the development of therapeutic agents for obesity or other MCH-mediated disorders.
  Genomics 07/2002; 79(6):785-92. · 3.02 Impact Factor
• Article: Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism.

  Donald J Marsh, Drew T Weingarth, Dawn E Novi, Howard Y Chen, Myrna E Trumbauer, Airu S Chen, Xiao-Ming Guan, Michael M Jiang, Yue Feng, Ramon E Camacho, [......], Hong Yu, Joseph M Metzger, Stephanie J Kuca, Lauren P Shearman, Shobhna Gopal-Truter, Douglas J MacNeil, Alison M Strack, D Euan MacIntyre, Lex H T Van der Ploeg, Su Qian
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  ABSTRACT: Melanin-concentrating hormone (MCH) is a cyclic 19-aa hypothalamic neuropeptide derived from a larger prohormone precursor of MCH (Pmch), which also encodes neuropeptide EI (NEI) and neuropeptide GE (NGE). Pmch-deficient (Pmch-/-) mice are lean, hypophagic, and have an increased metabolic rate. Transgenic mice overexpressing Pmch are hyperphagic and develop mild obesity. Consequently, MCH has been implicated in the regulation of energy homeostasis. The MCH 1 receptor (MCH1R) is one of two recently identified G protein-coupled receptors believed to be responsible for the actions of MCH. We evaluated the physiological role of MCH1R by generating MCH1R-deficient (Mch1r-/-) mice. Mch1r-/- mice have normal body weights, yet are lean and have reduced fat mass. Surprisingly, Mch1r-/- mice are hyperphagic when maintained on regular chow, and their leanness is a consequence of hyperactivity and altered metabolism. Consistent with the hyperactivity, Mch1r-/- mice are less susceptible to diet-induced obesity. Importantly, chronic central infusions of MCH induce hyperphagia and mild obesity in wild-type mice, but not in Mch1r-/- mice. We conclude that MCH1R is a physiologically relevant MCH receptor in mice that plays a role in energy homeostasis through multiple actions on locomotor activity, metabolism, appetite, and neuroendocrine function.
  Proceedings of the National Academy of Sciences 04/2002; 99(5):3240-5. · 9.68 Impact Factor