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Tung M Fong

Publications and source records attributed to Tung M Fong.

At least 19 recordsLinked to original sources
PubMed2006

Discovery of N-[(1S,2S)-3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2- {[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity.

The discovery of novel acyclic amide cannabinoid-1 receptor inverse agonists is described. They are potent, selective, orally bioavailable, and active in rodent models of food intake and body weight reduction. A major focus of the optimization process was to increase in vivo efficacy and to reduce the potential for formation of reactive metabolites. These efforts led to the identification of compound 48 for development as a clinical candidate for the treatment of obesity.

Animals↗
PubMed2006

Effects of the CB1 cannabinoid receptor inverse agonist AM251 on food intake and body weight in mice lacking mu-opioid receptors.

We used mu-opioid receptor-deficient (MOR-/-) mice to determine the effects of the CB1 cannabinoid receptor inverse agonist AM251 on feeding in the absence of MOR signaling. A single dose of AM251 at 0.6, 2 or 6 mg/kg caused similar dose-dependent suppression of food intake in wild-type and MOR-/- mice. Administration of AM251 at 3 mg/kg/day for 9 consecutive days also led to a similar reduction ( approximately 8%) in body weight in wild-type and MOR-/- mice. Our results suggest that MOR signaling is not necessary for cannabinoid-mediated effects on feeding and that physiological antagonism of opioid receptor tone might be required for the observed synergistic effects of a CB1 inverse agonist and an opioid receptor antagonist on feeding.

Animals↗
PubMed2006

The mu-opioid receptor subtype is required for the anorectic effect of an opioid receptor antagonist.

A diaryl ether derivative, (6-(4-{[(3-methylbutyl)amino]methyl}phenoxy)nicotinamide, was prepared and investigated for its biochemical properties at cloned opioid receptors and its pharmacological effects on animal feeding. The compound displaced [(3)H]DAMGO binding of human mu-opioid receptor, [(3)H]U-69593 of human kappa-opioid receptor, and [(3)H]DPDPE of human delta-opioid receptor with IC(50) values of 0.5+/-0.2 nM, 1.4+/-0.2 nM, and 71+/-15 nM, respectively. The compound also potently inhibited [(3)H]DAMGO binding of cloned mouse and rat mu-opioid receptors (IC(50) approximately 1 nM), and acted as a competitive antagonist in a cAMP functional assay using cultured cells expressing human or mouse mu-opioid receptors. Following a single oral administration in diet-induced obese mice (at 10 or 50 mg/kg) or rats (at 1, 3, or 10 mg/kg), the compound caused a dose-dependent suppression of acute food intake and body weight gain in both species. Importantly, the anorectic efficacy of the compound was mostly diminished in mice deficient in the mu-opioid receptor. Our results suggest an important role for the mu-opioid receptor subtype in animal feeding regulation and support the development of mu-selective antagonists as potential agents for treating human obesity.

Animals↗
PubMed2006

Effects of mutations at conserved TM II residues on ligand binding and activation of mouse 5-HT6 receptor.

An aspartate residue (Asp-72) in the transmembrane helix II of mouse 5-hydroxytryptamine-6 receptor (5-HT6) is conserved among most G protein-coupled receptors. We have examined the functional significance of this residue by site-directed mutagenesis. A single Asp --> Ala (D72A) mutation resulted in an 8-fold decrease in apparent affinity for 5-HT, and a 60-fold reduction in EC50 value of agonist-induced stimulation of adenylyl cyclase. A F69L/T70I/D72A triple mutant showed a 2-fold reduction in apparent affinity for 5-HT but complete loss of adenylyl cyclase stimulation. Binding of SB-258585 (4-iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzene-sulfonamide), a selective 5-HT6 antagonist, was mildly affected (2- to 4-fold decrease in affinity) in the two mutants. Our data suggest that Asp-72 and additional residues toward the intracellular side of TM II have a limited role in ligand binding but are critical for functional activation of the 5-HT6 receptor.

Amino Acid Sequence↗
PubMed2006

Galanin and galanin-like peptide differentially modulate neuronal activities in rat arcuate nucleus neurons.

Neuropeptides galanin and galanin-like peptide (GALP) share similar amino acid sequence and presumably interact with the same group of receptors, but they differentially regulate a variety of physiological and pathophysiological processes including metabolism and reproduction. Here we explored the neurophysiological basis of the in vivo differential effect between galanin and GALP by examining galanin and GALP modulation of neuronal activities of neurons in the arcuate nucleus (Arc), a brain region critically involved in energy homeostasis and reproductive function. We demonstrated that galanin and GALP inhibited excitatory and inhibitory postsynaptic currents in a similar way. In contrast, galanin and GALP differentially affected the intrinsic membrane property. In most recorded Arc neurons, galanin perfusion induced significant hyperpolarization of the resting membrane potential, which was not affected by GALP perfusion. In addition, galanin perfusion substantially suppressed the spontaneous spike firing in most Arc neurons, whereas in response to GALP perfusion, about half of the Arc neurons exhibited mild reduction in spontaneous spike firing and the other half showed enhancement. Furthermore, the Arc neurons that had been previously responsive to galanin perfusion no longer responded to galanin if co-applied with GALP, indicating that GALP can physiologically antagonize galanin effect. This differential effect appears to be mediated by G protein within the recorded cell, as the galanin effect on firing rate was abolished when the recorded cell was loaded with GDP-betaS, an agent that blocks G protein activity. Taken together, these differential effects of galanin and GALP may provide a neurophysiological mechanism through which galanin and GALP differentially regulate energy balance, reproductive function, and other physiological processes.

Action Potentials↗
PubMed2006

F200A substitution in the third transmembrane helix of human cannabinoid CB1 receptor converts AM2233 from receptor agonist to inverse agonist.

To investigate how specific amino acid residues affect human cannabinoid CB1 receptor binding and activation, CHO cell lines stably expressing wild type and the phenylalanine 200 to alanine mutant of human cannabinoid CB1 receptor (F200A) were examined. AM2233 functions as an agonist at the wild type receptor (EC50=0.93 nM), but behaves as an inverse agonist at F200A (EC50=4.8 nM). The F200A mutant has significantly lower forskolin-stimulated basal cAMP accumulation than that of the wild type, indicating that the F200A mutant possesses higher constitutive activity. F200 doesn't contribute substantially to the high affinity binding of AM2233 at human cannabinoid CB1 receptor. CP55940, HU-210 and Win55212-2 still function as agonists at the F200A mutant, with similar efficacy, potency, and apparent binding affinity for both wild type human cannabinoid CB1 receptor and F200A mutant. These data indicate that the phenylalanine 200 residue in human cannabinoid CB1 receptor is involved in the receptor activation induced by a specific class of agonists, and supports a model of agonist-structure-dependent conformational changes.

Alanine↗
PubMed2006

Neuronal activation in the hypothalamus and brainstem during feeding in rats.

We trained rats to a regime of scheduled feeding, in which food was available for only 2 hr each day. After 10 days, rats were euthanized at defined times relative to food availability, and their brains were analyzed to map Fos expression in neuronal populations to test the hypothesis that some populations are activated by hunger whereas others are activated by satiety signals. Fos expression accompanied feeding in several hypothalamic and brainstem nuclei. Food ingestion was critical for Fos expression in noradrenergic and non-noradrenergic cells in the nucleus tractus solitarii and area postrema and in the supraoptic nucleus, as well as in melanocortin-containing cells of the arcuate nucleus. However, anticipation of food alone activated other neurons in the arcuate nucleus and in the lateral and ventromedial hypothalamus, including orexin neurons. Thus orexigenic populations are strongly and rapidly activated at the onset of food presentation, followed rapidly by activity in anorexigenic populations when food is ingested.

Animals↗
PubMed2006

Fat and energy partitioning: longitudinal observations in leptin-treated adults homozygous for a Lep mutation.

OBJECTIVE: Partitioning of body energy content in the aleptinemic ob/ob mouse differs from that in wild-type mice, but it is not known whether parallel differences exist between humans with leptin (Lep) gene mutations and healthy adults. The objective of this study was to evaluate body composition in three leptin-treated Turkish adults homozygous for a missense mutation (C-->T substitution at codon 105 resulting in Arg-->Trp) of Lep. RESEARCH METHODS AND PROCEDURES: Subjects, one male and two female Turkish family members, were evaluated at baseline and treated for 18 months with r-MetHuLeptin. Patient data (fat mass, energy content) were compared with adult sex-specific predicted values (adjusted for weight, height, and age) derived in healthy control subjects. RESULTS: Weight loss with leptin treatment was substantial, ranging from 43.9% to 52.1%. At baseline and with leptin treatment, the two women had a fat mass and energy content similar (+/-12%) to predicted values. Baseline fat and energy content in the male patient was high compared with predicted values (e.g., fat +33%) but approached and reached normal values (e.g., fat, +2%) after 18 months of leptin therapy. DISCUSSION: Adult women with Lep mutations had body composition similar to normal women at baseline and with leptin treatment. In contrast, the man with a Lep mutation had high body fat in the untreated state but a normal male phenotype with leptin administration, possibly secondary to androgenic fat partitioning effects. Fat and energy partitioning can, thus, be quantitatively assessed and linked with potential hormonal mechanisms in humans with inherited disturbances in energy regulation.

Adult↗
PubMed2005

Interactions of human melanocortin 4 receptor with nonpeptide and peptide agonists.

Specific interactions of human melanocortin-4 receptor (hMC4R) with its nonpeptide and peptide agonists were studied using alanine-scanning mutagenesis. The binding affinities and potencies of two synthetic, small-molecule agonists (THIQ, MB243) were strongly affected by substitutions in transmembrane alpha-helices (TM) 2, 3, 6, and 7 (residues Glu(100), Asp(122), Asp(126), Phe(261), His(264), Leu(265), and Leu(288)). In addition, a I129A mutation primarily affected the binding and potency of THIQ, while F262A, W258A, Y268A mutations impaired interactions with MB243. By contrast, binding affinity and potency of the linear peptide agonist NDP-MSH were substantially reduced only in D126A and H264A mutants. Three-dimensional models of receptor-ligand complexes with their agonists were generated by distance-geometry using the experimental, homology-based, and other structural constraints, including interhelical H-bonds and two disulfide bridges (Cys(40)-Cys(279), Cys(271)-Cys(277)) of hMC4R. In the models, all pharmacophore elements of small-molecule agonists are spatially overlapped with the corresponding key residues (His(6), d-Phe(7), Arg(8), and Trp(9)) of the linear peptide: their charged amine groups interact with acidic residues from TM2 and TM3, similar to His(6) and Arg(6) of NDP-MSH; their substituted piperidines mimic Trp(9) of the peptide and interact with TM5 and TM6, while the d-Phe aromatic rings of all three agonists contact with Leu(133), Trp(258), and Phe(261) residues.

Amino Acid Sequence↗
PubMed2005

Synthesis and activity of 4,5-diarylimidazoles as human CB1 receptor inverse agonists.

Structure-activity relationship studies directed toward the optimization of 4,5-diarylimidazole-2-carboxamide analogs as human CB1 receptor inverse agonists resulted in the discovery of the two amide derivatives 24a and b (hCB1 IC50 = 6.1 and 4.0 nM) which also demonstrated efficacy in overnight feeding studies in the rat for reduction in both food intake and overall body weight.

Animals↗
PubMed2005

Synthesis and SAR of 5,6-diarylpyridines as human CB1 inverse agonists.

Structure-activity relationship studies for two series of 2-benzyloxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyridines having either a 3-cyano or 3-carboxamide moiety resulted in the preparation of the 2-(3,4-difluorobenzyloxy)-3-nitrile analog 10d and the 2-(3,4-difluorobenzyloxy)-3-(N-propylcarboxamide) analog 16c, (hCB1 IC(50)=1.3 and 1.7 nM, respectively) as potent and selective hCB1 inverse agonists. Their synthesis and biological activities are described herein.

Animals↗
PubMed2005

Advances in anti-obesity therapeutics.

Obesity is rapidly becoming an epidemic in developed countries. Currently available anti-obesity therapeutics are only modestly effective and are accompanied by significant adverse effects. In recent years, substantial advances have been made in the basic understanding of brain control of feeding behaviour and metabolism. As a result, several compounds have progressed to Phase III development, with additional compounds at various stages of Phase II development. Most of the late-stage development candidates are CNS agents, which reflects the consensus that the brain exerts a dominant control on feeding behaviour and peripheral metabolism through the autonomic nervous system. Homeostatic mechanisms encompassing hypothalamic/brainstem pathways have long been recognised in obesity research. In addition, non-homeostatic mechanisms encompassing the reward circuit and volitional control need to be targeted to control feeding behaviour and physical activity, especially in humans. While recognising the importance of CNS control, certain peripherally acting agents can affect mitochondrial metabolism, lipolysis, nutrient absorption or the vagal feedback pathway, such that these peripherally acting agents can potentially be combined with CNS agents to achieve maximal efficacy. It is expected that newer generations of anti-obesity therapeutics will be superior to existing agents and will facilitate lifestyle modification.

Animals↗
PubMed2004

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

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 groups also gained body weight at a rate faster than the control. Body composition analysis showed that the extra body weight gains in the treated animals were mostly due to increased fat accumulation. Since acute nalmefene treatment showed a trend toward a decrease rather than an increase in food intake, it is possible that the orexigenic effect of chronic oral administration of nalmefene was caused by pharmacologically active metabolites rather than the drug itself. Our results argue against the potential use of nalmefene for treating human obesity.

Administration, Oral↗
PubMed2004

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

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 dose of AM251 was further enhanced when co-administered with nalmefene. The results support a synergistic interaction between opioid and cannabinoid systems in regulating feeding behavior.

Animals↗
PubMed2004

Targeting metabolic syndrome.

Metabolic syndrome has been recognised as a cluster of risk factors contributing to the development of cardiovascular diseases. Different diagnostic criteria have been proposed and the consensus focuses on four major risk factors: obesity, diabetes, dyslipidaemia and hypertension. Although treatment options are available to treat each component separately, a highly effective agent for metabolic syndrome has yet to be developed. To explore the clinical definition of metabolic syndrome and potential molecular targets that can be modulated for treatment purpose, a meeting entitled 'Targeting Metabolic Syndrome' was organised in 2004 by IBC USA Conferences, Inc. This article highlights discussions related to the clinical correlates and pathophysiology of metabolic syndrome, and reviews some of the promising drug discovery efforts. Metabolic syndrome should be treatable and preventable if obesity and insulin resistance are well controlled. New regulatory guidelines need to be developed as new treatment options are being investigated. From a broad spectrum of potential mechanisms encompassing central nervous system targets and peripheral targets for pharmacological intervention, a few promising molecular targets have emerged. Modulating these is expected to treat at least some components of metabolic syndrome.

Animals↗
PubMed2003

The melanocortin system.

The melanocortin system consists of melanocortin peptides derived from the proopiomelanocortin gene, five melanocortin receptors, two endogenous antagonists, and two ancillary proteins. This review provides an abbreviated account of the basic biochemistry, pharmacology, and physiology of the melanocortin system and highlights progress made in four areas. In particular, recent pharmacological and genetic studies have affirmed the role of melanocortins in pigmentation, inflammation, energy homeostasis, and sexual function. Development of selective agonists and antagonists is expected to further facilitate the investigation of these complex physiological functions and provide an experimental basis for new pharmacotherapies.

Animals↗