Search results for: Douglas J. MacNeil

Items from 1 to 20 out of 28 results

article

Imidazopyridyl compounds as aldosterone synthase inhibitors

Brent R. Whitehead, Michael M.-C. Lo, Amjad Ali, Min K. Park, more

Bioorganic & Medicinal Chemistry Letters > 2017 > 27 > 2 > 143-146

The inhibition of aldosterone synthase (CYP11B2) may be an effective treatment of hypertension and heart failure, among other ailments. Previously reported benzimidazole CYP11B2 inhibitors led the way for bioisosteric imidazopyridines that are both potent and selective over CYP11B1.

article

Discovery of pyrimidine carboxamides as potent and selective CCK1 receptor agonists

Liping Wang, James A. Hubert, Susan J. Lee, Jie Pan, more

Bioorganic & Medicinal Chemistry Letters > 2011 > 21 > 10 > 2911-2915

A series of six-membered heterocycle carboxamides were synthesized and evaluated as cholecystokinin 1 receptor (CCK1R) agonists. A pyrimidine core proved to be the best heterocycle, and SAR studies resulted in the discovery of analog 5, a potent and structurally diverse CCK1R agonist.

article

Pancreatic polypeptide enhances colonic muscle contraction and fecal output through neuropeptide Y Y4 receptor in mice

Ryuichi Moriya, Toru Fujikawa, Junko Ito, Takashi Shirakura, more

European Journal of Pharmacology > 2010 > 627 > 1-3 > 258-264

Pancreatic polypeptide is released mainly from the pancreas, and is thought to be one of the major endogenous agonists of the neuropeptide Y Y ₄ receptor. Pancreatic polypeptide has been shown to stimulate colonic muscle contraction, but whether pancreatic polypeptide has in vivo functional activity with respect to colonic transit is unclear. The present report investigated the effects of...

article

Melanin-concentrating hormone 1-receptor antagonist suppresses body weight gain correlated with high receptor occupancy levels in diet-induced obesity mice

Masahiko Ito, Akane Ishihara, Akira Gomori, Shinichiro Egashira, more

European Journal of Pharmacology > 2009 > 624 > 1-3 > 77-83

Melanin-concentrating hormone (MCH), which is a neuropeptide expressed in the hypothalamus of the brain, is involved in regulating feeding behavior and energy homeostasis via the MCH ₁ receptor in rodents. It is widely considered that MCH ₁ receptor antagonists are worthy of development for medical treatment of obesity. Here we report on the development of an ex vivo receptor occupancy...

article

MCH receptor peptide agonists and antagonists

Douglas J. MacNeil, Maria A. Bednarek

Peptides > 2009 > 30 > 11 > 2008-2013

Melanin-concentrating hormone (MCH) is an important neuropeptide hormone involved in multiple physiological processes. Peptide derivatives of MCH have been developed as tools to aid research including potent radioligands, receptor selective agonists, and potent antagonists. These tools have been used to further understand the role of MCH in physiology, primarily in rodents. However, the tools could...

article

Identification of novel and orally active spiroindoline NPY Y5 receptor antagonists

Toshihiro Sakamoto, Minoru Moriya, Yuji Haga, Toshiyuki Takahashi, more

Bioorganic & Medicinal Chemistry Letters > 2009 > 19 > 6 > 1564-1568

A series of spiroindoline-3,4′-piperidine derivatives were synthesized and evaluated for their binding affinities and antagonistic activities at Y5 receptors. Potent Y5 antagonists were tested for their oral bioavailabilities and brain penetration in rats. Some of the antagonists showed good oral bioavailability and/or good brain penetration. In particular, compound 6e was orally bioavailable and...

article

2-Substituted piperazine-derived imidazole carboxamides as potent and selective CCK1R agonists for the treatment of obesity

Richard Berger, Cheng Zhu, Alexa R. Hansen, Bart Harper, more

Bioorganic & Medicinal Chemistry Letters > 2008 > 18 > 17 > 4833-4837

The discovery and structure–activity relationship of 1,2-diarylimidazole piperazine carboxamides bearing polar side chains as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described. Optimization of this series resulted in the discovery of isopropyl carboxamide 40, a CCK1R agonist with sub-nanomolar functional and binding activity as well as excellent potency in a mouse overnight...

article

Characterization of a novel and selective cannabinoid CB1 receptor inverse agonist, Imidazole 24b, in rodents

Lauren P. Shearman, D. Sloan Stribling, Ramon E. Camacho, Kimberly M. Rosko, more

European Journal of Pharmacology > 2008 > 579 > 1-3 > 215-224

We document in vitro and in vivo effects of a novel, selective cannabinoid CB ₁ receptor inverse agonist, Imidazole 24b (5-(4-chlorophenyl)-N-cyclohexyl-4-(2,4-dichlorophenyl)-1-methyl-imidazole-2-carboxamide). The in vitro binding affinity of Imidazole 24b for recombinant human and rat CB ₁ receptor is 4 and 10 nM, respectively. Imidazole 24b binds to human cannabinoid CB ₂ ...

article

2-Aminoquinoline melanin-concentrating hormone (MCH)1R antagonists

Jinlong Jiang, Myle Hoang, Jonathan R. Young, Danny Chaung, more

Bioorganic & Medicinal Chemistry Letters > 2006 > 16 > 20 > 5270-5274

A series of 2-aminoquinoline compounds was prepared and evaluated in MCH1R binding and functional antagonist assays. Small dialkyl, methylalkyl, methylcycloalkyl, and cyclic amines were tolerated at the quinoline 2-position. The in vivo efficacy of compound 12 was explored and compared to that of a related inactive analog to determine their effects on food intake and body weight in rodents.

article

4-Aminoquinoline melanin-concentrating hormone 1-receptor (MCH1R) antagonists

Jinlong Jiang, Peter Lin, Myle Hoang, Lehua Chang, more

Bioorganic & Medicinal Chemistry Letters > 2006 > 16 > 20 > 5275-5279

Structure–activity relationships of a 4-aminoquinoline MCH1R antagonist lead series were explored by synthesis of analogs with modifications at the 2-, 4-, and 6-positions of the original HTS hit. Improvements to the original screening lead included lipophilic groups at the 2-position and biphenyl, cyclohexyl phenyl, and hydrocinnamyl carboxamides at the 6-position. Modifications of the 4-amino group...

article

Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults

Ngozi Erondu, Ira Gantz, Bret Musser, Shailaja Suryawanshi, more

Cell Metabolism > 2006 > 4 > 4 > 275-282

Neuropeptide Y (NPY) is a potent orexigenic neuropeptide, and antagonism of NPY Y1 and NPY Y5 receptors (NPYxR) is considered a potentially important anti-obesity drug target. We tested the hypothesis that blockade of the NPY5R will lead to weight loss in humans using MK-0557, a potent, highly selective, orally active NPY5R antagonist. The initial series of experiments reported herein, including a...

article

Detailed pharmacological characterization of GT-2331 for the rat histamine H3 receptor

Sayaka Ito, Ryo Yoshimoto, Yasuhisa Miyamoto, Yuko Mitobe, more

European Journal of Pharmacology > 2006 > 529 > 1-3 > 40-46

Histamine H ₃ receptor antagonists are potential therapeutic agents for cognitive dysfunction, epilepsy, hypersomnia and obesity. GT-2331 (4-[(R,R)-2-(5,5-dimethyl-1-hexynyl)cyclopropyl]-1H-imidazole) was originally identified as a potent histamine H ₃ receptor antagonist. However, recent reports demonstrated a complex pharmacology for GT-2331. To further understand the pharmacological...

article

Chronic administration of nalmefene leads to increased food intake and body weight gain in mice

Richard Z. Chen, Ruey-Ruey C. Huang, Chun-Pyn Shen, Douglas J. MacNeil, more

European Journal of Pharmacology > 2004 > 495 > 1 > 63-66

Nalmefene is an orally available opioid receptor antagonist that has been shown to suppress appetite in humans, but its effects on chronic food intake and body weight remain unclear. Here, we report that chronic (21-day) oral administration of nalmefene at 2 or 10 mg/kg/day in diet-induced obese (DIO) mice led to significant increases (9-11%) in cumulative food intake. Mice in the nalmefene-treated...

article

Expression, refolding, and purification of recombinant human phosphodiesterase 3B: definition of the N-terminus of the catalytic core

Jeffrey P. Varnerin, Christine C. Chung, Sangita B. Patel, Giovanna Scapin, more

Protein Expression and Purification > 2004 > 35 > 2 > 225-236

We have developed an expression, refolding, and purification protocol for the catalytic domain of human Phosphodiesterase 3B (PDE3B). High level expression in Escherichia coli has been achieved with yields of up to 20mg/L. The catalytic domain of the enzyme was purified by affinity chromatography utilizing a novel affinity ligand. PDE3B, purified by affinity chromatography, with no single impurity...

article

Synergistic effects of cannabinoid inverse agonist AM251 and opioid antagonist nalmefene on food intake in mice

Richard Z. Chen, Ruey-Ruey C. Huang, Chun-Pyn Shen, Douglas J. MacNeil, more

Brain Research > 2004 > 999 > 2 > 227-230

Oral administration of the opioid antagonist nalmefene alone (up to 20 mg/kg) failed to show a significant effect on acute food intake in mice. However, combined oral dosing of nalmefene and subthreshold doses of AM251, a cannabinoid CB1 receptor inverse agonist, led to a significant reduction in food intake in both lean and diet-induced obese (DIO) mice. Furthermore, the anorectic effect of a high...

article

The role of tryptophan 1072 in human PDE3B inhibitor binding

Christine Chung, Jeffrey P. Varnerin, Nancy R. Morin, Douglas J. MacNeil, more

Biochemical and Biophysical Research Communications > 2003 > 307 > 4 > 1045-1050

The catalytic domain of recombinant human PDE3B was expressed in Escherichia coli as inclusion bodies and refolded to form active enzyme. A mutation at tryptophan 1072 in PDE3B disrupts inhibitor binding, but has minimal effect on cAMP hydrolysis. The W1072A mutation caused a 158-fold decrease in affinity for cilostamide, a 740-fold decrease for cGMP, and a 15-fold decrease in affinity for IBMX. The...

article

''The role of melanocortins in body weight regulation: opportunities for the treatment of obesity''

Douglas J. MacNeil, Andrew D. Howard, Xiaoming Guan, Tung M. Fong, more

European Journal of Pharmacology > 2002 > 450 > 1 > 93-109

Five G-protein-coupled melanocortin receptors (MC ₁ -MC ₅ ) are expressed in mammalian tissues. The melanocortin receptors support diverse physiological functions, including the regulation of hair color, adrenal function, energy homeostasis, feed efficiency, sebaceous gland lipid production and immune and sexual function. The melanocortins (adrenocorticotropic hormone (ACTH), α-melanocyte-stimulating...

article

Novel Sesquiterpenoids from the Fermentation of Xylaria p ersicaria Are Selective Ligands for the NPY Y5 Receptor

Cameron J. Smith, Nancy R. Morin, Gerald F. Bills, Anne W. Dombrowski, more

The Journal of Organic Chemistry > 2002 > 67 > 14 > 5001 - 5004

article

Melanin-Concentrating Hormone Receptor Subtypes 1 and 2: Species-Specific Gene Expression

Carina P. Tan, Hideki Sano, Hisashi Iwaasa, Jie Pan, more

Genomics > 2002 > 79 > 6 > 785-792

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...

article

Synthesis and Biological Evaluation in Vitro of Selective, High Affinity Peptide Antagonists of Human Melanin-Concentrating Hormone Action at Human Melanin-Concentrating Hormone Receptor 1

Maria A. Bednarek, Donna L. Hreniuk, Carina Tan, Oksana C. Palyha, more

Biochemistry > 2002 > 41 > 20 > 6383 - 6390

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INFONA - science communication portal

Search results for: Douglas J. MacNeil

Imidazopyridyl compounds as aldosterone synthase inhibitors

Discovery of pyrimidine carboxamides as potent and selective CCK1 receptor agonists

Pancreatic polypeptide enhances colonic muscle contraction and fecal output through neuropeptide Y Y4 receptor in mice

Melanin-concentrating hormone 1-receptor antagonist suppresses body weight gain correlated with high receptor occupancy levels in diet-induced obesity mice

MCH receptor peptide agonists and antagonists

Identification of novel and orally active spiroindoline NPY Y5 receptor antagonists

2-Substituted piperazine-derived imidazole carboxamides as potent and selective CCK1R agonists for the treatment of obesity

Characterization of a novel and selective cannabinoid CB1 receptor inverse agonist, Imidazole 24b, in rodents

2-Aminoquinoline melanin-concentrating hormone (MCH)1R antagonists

4-Aminoquinoline melanin-concentrating hormone 1-receptor (MCH1R) antagonists

Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults

Detailed pharmacological characterization of GT-2331 for the rat histamine H3 receptor

Chronic administration of nalmefene leads to increased food intake and body weight gain in mice

Expression, refolding, and purification of recombinant human phosphodiesterase 3B: definition of the N-terminus of the catalytic core

Synergistic effects of cannabinoid inverse agonist AM251 and opioid antagonist nalmefene on food intake in mice

The role of tryptophan 1072 in human PDE3B inhibitor binding

''The role of melanocortins in body weight regulation: opportunities for the treatment of obesity''

Novel Sesquiterpenoids from the Fermentation of Xylaria p ersicaria Are Selective Ligands for the NPY Y5 Receptor

Melanin-Concentrating Hormone Receptor Subtypes 1 and 2: Species-Specific Gene Expression

Synthesis and Biological Evaluation in Vitro of Selective, High Affinity Peptide Antagonists of Human Melanin-Concentrating Hormone Action at Human Melanin-Concentrating Hormone Receptor 1

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