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Chris G Kruse - One of the best experts on this subject based on the ideXlab platform.
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synthesis sar and intramolecular hydrogen bonding pattern of 1 3 5 trisubstituted 4 5 dihydropyrazoles as potent cannabinoid CB1 Receptor Antagonists
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Josephus H M Lange, Arnold Den P Hartog, Martina A W Van Der Neut, Bernard J Van Vliet, Herman H Van Stuivenberg, Henri C Wals, Jan Hoogendoorn, Chris G KruseAbstract:Abstract The synthesis, structure–activity relationship (SAR) studies and intramolecular hydrogen bonding pattern of 1,3,5-trisubstituted 4,5-dihydropyrazoles are described. The target compounds 6–18 represent a novel class of potent and selective CB1 Receptor Antagonists. Based on X-ray diffraction data, the orally active 17 is shown to elicit a different intramolecular H-bonding mode as compared to ibipinabant (3) and SLV330 (4).
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synthesis and sar of 1 4 5 6 tetrahydropyridazines as potent cannabinoid CB1 Receptor Antagonists
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Josephus H M Lange, Arnold Den P Hartog, Martina A W Van Der Neut, Bernard J Van Vliet, Chris G KruseAbstract:The synthesis and structure-activity relationship studies of 1,4,5,6-tetrahydropyridazines are described. The target compounds 3-5 represent a novel class of potent and selective CB1 Receptor Antagonists.
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cannabinoid CB1 Receptor Antagonists in therapeutic and structural perspectives
Chemical Record, 2008Co-Authors: Josephus H M Lange, Chris G KruseAbstract:The observed antiobesity effect of rimonabant (1) in a pharmacological rodent model 10 years ago has led to a surge in the search for novel cannabinoid CB1 Antagonists as a new therapeutic target for the treatment of obesity. Rimonabant showed clinical efficacy in the treatment of obesity and also improved cardiovascular and metabolic risk factors. Cannabinoid CB1 Receptor Antagonists have also good prospects in other therapeutic areas, including smoking and alcohol addiction as well as cognitive impairment. Solvay's research achievements in this fast-moving field are reported in relation with the current state of the art. Several medicinal chemistry strategies have been pursued. The application of the concept of conformational constraint led to the discovery of more rigid analogs of the prototypic CB1 Receptor antagonist rimonabant. Replacement of the central heterocyclic pyrazole ring in rimonabant yielded imidazoles, triazoles, and thiazoles as selective CB1 Receptor Antagonists. Dedicated medium-throughput screening efforts delivered one 3,4-diarylpyrazoline hit. Its poor pharmacokinetic properties were successfully optimized which led to the discovery of orally active and highly CB1/CB2 Receptor selective analogs in this series. Regioisomeric 1,5-diarylpyrazolines, 1,2-diarylimidazolines, and water-soluble imidazoles have been designed as novel CB1 Receptor antagonist structure classes.
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novel 3 4 diarylpyrazolines as potent cannabinoid CB1 Receptor Antagonists with lower lipophilicity
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Josephus H M Lange, Herman H Van Stuivenberg, Henri C Wals, Willem Veerman, Bob Stork, Hein K A C Coolen, Andrew C Mccreary, Tiny J P Adolfs, Chris G KruseAbstract:Abstract Novel 3,4-diarylpyrazolines 1 as potent CB1 Receptor Antagonists with lipophilicity lower than that of SLV319 are described. The key change is the replacement of the arylsulfonyl group in the original series by a dialkylaminosulfonyl moiety. The absolute configuration (4S) of eutomer 24 was established by X-ray diffraction analysis and 24 showed a close molecular fit with rimonabant in a CB1 Receptor-based model. Compound 17 exhibited the highest CB1 Receptor affinity (Ki = 24 nM) in this series, as well as very potent CB1 antagonistic activity (pA2 = 8.8) and a high CB1/CB2 subtype selectivity (∼147-fold).
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Recent advances in CB1 cannabinoid Receptor Antagonists.
Current opinion in drug discovery & development, 2004Co-Authors: Josephus H M Lange, Chris G KruseAbstract:Cannabinoid CB1 Receptor Antagonists are currently the subject of intensive research due to their highly promising therapeutic prospects. Novel chemical entities having CB1 antagonistic properties have recently been disclosed by several pharmaceutical companies and some academic research groups, some of which are close structural analogs of the leading compound rimonabant (SR-141716A; Sanofi-Synthelabo). A considerable number of these CB1 Antagonists are bioisosteres that are derived from rimonabant by the replacement of the pyrazole moiety with an alternative heterocycle. As well as these achiral compounds, Solvay Pharmaceuticals have disclosed a novel class of chiral pyrazolines that are potent and CB1/CB2 subtype-selective cannabinoid Receptor Antagonists, in which the interactions with the CB1 Receptor are highly stereoselective.
Alexandros Makriyannis - One of the best experts on this subject based on the ideXlab platform.
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effects of the CB1 Receptor Antagonists am6545 and am4113 on insulin resistance in a high fructose high salt rat model of metabolic syndrome
Medicina-lithuania, 2020Co-Authors: Basma G Eid, Thikryat Neamatallah, Abeer Hanafy, Hany M Elbassossy, Hibah M Aldawsari, Kiran Vemuri, Alexandros MakriyannisAbstract:Background and Objectives: Insulin resistance (IR) is a serious condition leading to development of diabetes and cardiovascular complications. Hyper-activation of cannabinoid Receptors-1 (CB1) has been linked to the development of metabolic disorders such as IR. Therefore, the effect of blocking CB1 on the development of IR was investigated in the present study. Materials and Methods: A 12-week high-fructose/high-salt feeding model of metabolic syndrome was used to induce IR in male Wistar rats. For this purpose, two different CB1-Antagonists were synthesized and administered to the rats during the final four weeks of the study, AM6545, the peripheral neutral antagonist and AM4113, the central neutral antagonist. Results: High-fructose/salt feeding for 12 weeks led to development of IR while both AM6545 and AM4113, administered in the last 4 weeks, significantly inhibited IR. This was correlated with increased animal body weight wherein both AM6545 and AM4113 decreased body weight in IR animals but with loss of IR/body weight correlation. While IR animals showed significant elevations in serum cholesterol and triglycerides with no direct correlation with IR, both AM6545 and AM4113 inhibited these elevations, with direct IR/cholesterol correlation in case of AM6545. IR animals had elevated serum uric acid, which was reduced by both AM6545 and AM4113. In addition, IR animals had decreased adiponectin levels and elevated liver TNFα content with strong IR/adiponectin and IR/TNFα correlations. AM6545 inhibited the decreased adiponectin and the increased TNFα levels and retained the strong IR/adiponectin correlation. However, AM4113 inhibited the decreased adiponectin and the increased TNFα levels, but with loss of IR/adiponectin and IR/TNFα correlations. Conclusions: Both CB1 neutral Antagonists alleviated IR peripherally, and exerted similar effects on rats with metabolic syndrome. They also displayed anti-dyslipidemic, anti-hyperurecemic and anti-inflammatory effects. Overall, these results should assist in the development of CB1 neutral Antagonists with improved safety profiles for managing metabolic disorders.
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a novel peripherally restricted cannabinoid Receptor antagonist am6545 reduces food intake and body weight but does not cause malaise in rodents
British Journal of Pharmacology, 2010Co-Authors: Nina L Cluny, V.k. Vemuri, Adam P Chambers, Cheryl L Limebeer, H Bedard, Jodianne T Wood, Beat Lutz, Andreas Zimmer, Linda A Parker, Alexandros MakriyannisAbstract:BACKGROUND AND PURPOSE Cannabinoid CB1 Receptor Antagonists reduce food intake and body weight, but clinical use in humans is limited by effects on the CNS. We have evaluated a novel cannabinoid antagonist (AM6545) designed to have limited CNS penetration, to see if it would inhibit food intake in rodents, without aversive effects. EXPERIMENTAL APPROACH Cannabinoid Receptor binding studies, cAMP assays, brain penetration studies and gastrointestinal motility studies were carried out to assess the activity profile of AM6545. The potential for AM6545 to induce malaise in rats and the actions of AM6545 on food intake and body weight were also investigated. KEY RESULTS AM6545 binds to CB1 Receptors with a Ki of 1.7 nM and CB2 Receptors with a Ki of 523 nM. AM6545 is a neutral antagonist, having no effect on cAMP levels in transfected cells and was less centrally penetrant than AM4113, a comparable CB1 Receptor antagonist. AM6545 reversed the effects of WIN55212-2 in an assay of colonic motility. In contrast to AM251, AM6545 did not produce conditioned gaping or conditioned taste avoidance in rats. In rats and mice, AM6545 dose-dependently reduced food intake and induced a sustained reduction in body weight. The effect on food intake was maintained in rats with a complete subdiaphragmatic vagotomy. AM6545 inhibited food intake in CB1 Receptor gene-deficient mice, but not in CB1/CB2 Receptor double knockout mice. CONCLUSIONS AND IMPLICATIONS Peripherally active, cannabinoid Receptor Antagonists with limited brain penetration may be useful agents for the treatment of obesity and its complications.
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potential anxiogenic effects of cannabinoid CB1 Receptor Antagonists inverse agonists in rats comparisons between am4113 am251 and the benzodiazepine inverse agonist fg 7142
European Neuropsychopharmacology, 2010Co-Authors: K S Sink, V.k. Vemuri, Alexandros Makriyannis, K N Segovia, Lyndsey E Collins, Etan J Markus, J Sink, Patrick A Randall, Merce Correa, John D SalamoneAbstract:Cannabinoid CB1 inverse agonists suppress food-motivated behaviors, but may also induce psychiatric effects such as depression and anxiety. To evaluate behaviors potentially related to anxiety, the present experiments assessed the CB1 inverse agonist AM251 (2.0-8.0 mg/kg), the CB1 antagonist AM4113 (3.0-12.0 mg/kg), and the benzodiazepine inverse agonist FG-7142 (10.0-20.0 mg/kg), using the open field test and the elevated plus maze. Although all three drugs affected open field behavior, these effects were largely due to actions on locomotion. In the elevated plus maze, FG-7142 and AM251 both produced anxiogenic effects. FG-7142 and AM251 also significantly increased c-Fos activity in the amygdala and nucleus accumbens shell. In contrast, AM4113 failed to affect performance in the plus maze, and did not induce c-Fos immunoreactivity. The weak effects of AM4113 are consistent with biochemical data showing that AM4113 induces little or no intrinsic cellular activity. This research may lead to the development of novel appetite suppressants with reduced anxiogenic effects.
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intracerebroventricular administration of cannabinoid CB1 Receptor Antagonists am251 and am4113 fails to alter food reinforced behavior in rats
Psychopharmacology, 2009Co-Authors: V.k. Vemuri, Alexandros Makriyannis, K S Sink, K N Segovia, Lyndsey E Collins, Eric J Nunes, Ganesh A Thakur, John D SalamoneAbstract:Rationale Drugs that interfere with cannabinoid CB1 transmission suppress food-motivated behaviors and may be useful as appetite suppressants, but there is uncertainty about the locus of action for the feeding-suppression effects of these drugs.
Gyorgy Bagdy - One of the best experts on this subject based on the ideXlab platform.
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CB1 Receptor Antagonists new discoveries leading to new perspectives
Acta Physiologica, 2012Co-Authors: Eszter Kirilly, Gyorgy Bagdy, Xenia GondaAbstract:CB(1) Receptor Antagonists were among the most promising drug targets in the last decade. They have been explored and found to be effective as therapeutic agents for obesity and related cardiometabolic problems; however, use of rimonabant, the first marketed CB(1) Receptor antagonist, has been suspended because of its anxiogenic and depressogenic side effects. Because some other antiobesity drugs, like dexfenfluramine or sibutramine, were also suspended, the unmet need for drugs that reduce body weight became enormous. One approach that emerged was the use of CB(1) Receptor Antagonists that poorly cross the blood brain barrier, the second, the development of neutral Antagonists instead of inverse agonists, and the third, use of personalized medicine, namely the selection of the patient population without psychiatric side effects. In this review, we dissect the peripheral and central mechanisms involved in the effects of CB(1) Receptor Antagonists and argue that central mechanisms are more or less involved in most cardiometabolic therapeutic effects and thus, among patients with unsatisfactory therapeutic response to compounds with peripheral action, centrally acting Antagonists may be needed. An analysis of pharmacogenetic factors may help to identify persons who are at no or low risk for psychiatric adverse effects. Here, we present the models and identify molecular mechanisms and Receptors involved in the effects of stress-, anxiety- and depression-related neurocircuitries sensitive to CB(1) Receptor Antagonists, like the serotonergic, noradrenergic and dopaminergic systems, which are not only regulated by CB(1) Receptors, but also regulate the synthesis of the endocannabinoid 2-arachidonoyl-glycerol.
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the rise and fall of CB1 Receptor Antagonists possible future perspectives
BMC Pharmacology, 2011Co-Authors: Gyorgy BagdyAbstract:Cannabinoid type-1 (CB1) Receptor Antagonists were among the most promising drug targets in the last decade. They have been explored and found to be effective as therapeutic agents for obesity and related cardiometabolic problems, including e.g. dyslipidaemias, diabetes, and metabolic syndrome. However, the use of rimonabant, the first marketed CB1 Receptor antagonist, has been suspended due to its anxiogenic and depressogenic side effects, which were present in about 20–30% of the patients, i.e. a 2.5–3-fold increase compared to placebo. Since some other anti-obesity drugs like dexfenfluramine or sibutramine were also suspended, the unmet need for drugs that reduce body weight became enormous. One approach that emerged was the development of peripheral CB1 Receptor Antagonists that poorly cross the blood brain barrier, the second, the development of neutral Antagonists instead of inverse agonists, and the third, the selection of the patient population with reduced risk for psychiatric side effects. An analysis regarding peripheral and central mechanisms involved in the effects of CB1 Receptor Antagonists strongly suggest that central mechanisms are more or less involved in most cardiometabolic therapeutic effects and thus, among patients with unsatisfactory therapeutic response to compounds with peripheral action, centrally acting Antagonists may be needed. Based on our existing knowledge concerning the role of genetic, phenotypic and environmental factors the selection of persons who are at no or low risk for psychiatric adverse effects may be possible. Molecular mechanisms and Receptors involved in the effects of stress and anxiety-related neurocircuitries sensitive to CB1 Receptor Antagonists, like the serotonergic and noradrenergic systems which regulate the synthesis of the endocannabinoid 2-arachydonoyl-glycerol mediated by 5-HT2C and α1 Receptors can be identified [1]. Furthermore, variants of the serotonin transporter and the CB1 Receptor genes have been shown to modulate stress-induced anxiety in human studies [1]. In conclusion, development of peripherally acting, or the use of personalised medicine for centrally acting CB1 Receptor Antagonists are promising approaches with diverse advantages.
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personalized medicine can pave the way for the safe use of CB1 Receptor Antagonists
Trends in Pharmacological Sciences, 2011Co-Authors: Judit Lazary, Gyorgy Bagdy, Gabriella Juhasz, Laszlo HunyadyAbstract:Antagonists of cannabinoid type-1 (CB 1 ) Receptors have been explored as therapeutic agents for obesity and addiction. However, use of rimonabant (the first marketed CB 1 Receptor antagonist) has been suspended due to its anxiogenic and depressive side effects (including suicide risk). Recent genomic studies provide evidence that variants of the CB 1 Receptor gene (CNR1) alone or in combination with the gene of the serotonin transporter (SLC6A4) contribute to the development of anxiety and/or depression, suggesting that high-risk individuals could be identified through genetic testing. In this review, we argue that identification of high-risk individuals by a combination of genomic screening, previous risk phenotype, and environmental risk factors offers a promising method for the safe use of centrally acting CB 1 Receptor Antagonists. We summarize endocannabinoid signaling in pathways related to anxiety and depression, identify the serotonergic system as the most likely candidate to mediate the side effects of CB 1 Receptor Antagonists, and propose that poloymorphisms in CNR1 , SLC6A4 and certain CYP 450 enzymes could help to identify individuals who may benefit from treatment with CB 1 Receptor antagonist without psychiatric side effects.
V.k. Vemuri - One of the best experts on this subject based on the ideXlab platform.
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a novel peripherally restricted cannabinoid Receptor antagonist am6545 reduces food intake and body weight but does not cause malaise in rodents
British Journal of Pharmacology, 2010Co-Authors: Nina L Cluny, V.k. Vemuri, Adam P Chambers, Cheryl L Limebeer, H Bedard, Jodianne T Wood, Beat Lutz, Andreas Zimmer, Linda A Parker, Alexandros MakriyannisAbstract:BACKGROUND AND PURPOSE Cannabinoid CB1 Receptor Antagonists reduce food intake and body weight, but clinical use in humans is limited by effects on the CNS. We have evaluated a novel cannabinoid antagonist (AM6545) designed to have limited CNS penetration, to see if it would inhibit food intake in rodents, without aversive effects. EXPERIMENTAL APPROACH Cannabinoid Receptor binding studies, cAMP assays, brain penetration studies and gastrointestinal motility studies were carried out to assess the activity profile of AM6545. The potential for AM6545 to induce malaise in rats and the actions of AM6545 on food intake and body weight were also investigated. KEY RESULTS AM6545 binds to CB1 Receptors with a Ki of 1.7 nM and CB2 Receptors with a Ki of 523 nM. AM6545 is a neutral antagonist, having no effect on cAMP levels in transfected cells and was less centrally penetrant than AM4113, a comparable CB1 Receptor antagonist. AM6545 reversed the effects of WIN55212-2 in an assay of colonic motility. In contrast to AM251, AM6545 did not produce conditioned gaping or conditioned taste avoidance in rats. In rats and mice, AM6545 dose-dependently reduced food intake and induced a sustained reduction in body weight. The effect on food intake was maintained in rats with a complete subdiaphragmatic vagotomy. AM6545 inhibited food intake in CB1 Receptor gene-deficient mice, but not in CB1/CB2 Receptor double knockout mice. CONCLUSIONS AND IMPLICATIONS Peripherally active, cannabinoid Receptor Antagonists with limited brain penetration may be useful agents for the treatment of obesity and its complications.
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potential anxiogenic effects of cannabinoid CB1 Receptor Antagonists inverse agonists in rats comparisons between am4113 am251 and the benzodiazepine inverse agonist fg 7142
European Neuropsychopharmacology, 2010Co-Authors: K S Sink, V.k. Vemuri, Alexandros Makriyannis, K N Segovia, Lyndsey E Collins, Etan J Markus, J Sink, Patrick A Randall, Merce Correa, John D SalamoneAbstract:Cannabinoid CB1 inverse agonists suppress food-motivated behaviors, but may also induce psychiatric effects such as depression and anxiety. To evaluate behaviors potentially related to anxiety, the present experiments assessed the CB1 inverse agonist AM251 (2.0-8.0 mg/kg), the CB1 antagonist AM4113 (3.0-12.0 mg/kg), and the benzodiazepine inverse agonist FG-7142 (10.0-20.0 mg/kg), using the open field test and the elevated plus maze. Although all three drugs affected open field behavior, these effects were largely due to actions on locomotion. In the elevated plus maze, FG-7142 and AM251 both produced anxiogenic effects. FG-7142 and AM251 also significantly increased c-Fos activity in the amygdala and nucleus accumbens shell. In contrast, AM4113 failed to affect performance in the plus maze, and did not induce c-Fos immunoreactivity. The weak effects of AM4113 are consistent with biochemical data showing that AM4113 induces little or no intrinsic cellular activity. This research may lead to the development of novel appetite suppressants with reduced anxiogenic effects.
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intracerebroventricular administration of cannabinoid CB1 Receptor Antagonists am251 and am4113 fails to alter food reinforced behavior in rats
Psychopharmacology, 2009Co-Authors: V.k. Vemuri, Alexandros Makriyannis, K S Sink, K N Segovia, Lyndsey E Collins, Eric J Nunes, Ganesh A Thakur, John D SalamoneAbstract:Rationale Drugs that interfere with cannabinoid CB1 transmission suppress food-motivated behaviors and may be useful as appetite suppressants, but there is uncertainty about the locus of action for the feeding-suppression effects of these drugs.
Adam P Chambers - One of the best experts on this subject based on the ideXlab platform.
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a novel peripherally restricted cannabinoid Receptor antagonist am6545 reduces food intake and body weight but does not cause malaise in rodents
British Journal of Pharmacology, 2010Co-Authors: Nina L Cluny, V.k. Vemuri, Adam P Chambers, Cheryl L Limebeer, H Bedard, Jodianne T Wood, Beat Lutz, Andreas Zimmer, Linda A Parker, Alexandros MakriyannisAbstract:BACKGROUND AND PURPOSE Cannabinoid CB1 Receptor Antagonists reduce food intake and body weight, but clinical use in humans is limited by effects on the CNS. We have evaluated a novel cannabinoid antagonist (AM6545) designed to have limited CNS penetration, to see if it would inhibit food intake in rodents, without aversive effects. EXPERIMENTAL APPROACH Cannabinoid Receptor binding studies, cAMP assays, brain penetration studies and gastrointestinal motility studies were carried out to assess the activity profile of AM6545. The potential for AM6545 to induce malaise in rats and the actions of AM6545 on food intake and body weight were also investigated. KEY RESULTS AM6545 binds to CB1 Receptors with a Ki of 1.7 nM and CB2 Receptors with a Ki of 523 nM. AM6545 is a neutral antagonist, having no effect on cAMP levels in transfected cells and was less centrally penetrant than AM4113, a comparable CB1 Receptor antagonist. AM6545 reversed the effects of WIN55212-2 in an assay of colonic motility. In contrast to AM251, AM6545 did not produce conditioned gaping or conditioned taste avoidance in rats. In rats and mice, AM6545 dose-dependently reduced food intake and induced a sustained reduction in body weight. The effect on food intake was maintained in rats with a complete subdiaphragmatic vagotomy. AM6545 inhibited food intake in CB1 Receptor gene-deficient mice, but not in CB1/CB2 Receptor double knockout mice. CONCLUSIONS AND IMPLICATIONS Peripherally active, cannabinoid Receptor Antagonists with limited brain penetration may be useful agents for the treatment of obesity and its complications.
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cannabinoid cb 1 Receptor antagonist am 251 causes a sustained reduction of daily food intake in the rat
Physiology & Behavior, 2004Co-Authors: Adam P Chambers, Keith A Sharkey, Henry S KoopmansAbstract:Cannabinoid (CB)1 Receptors are present throughout the nervous system, including several areas implicated in the control of food intake. Central and peripheral administration of CB1 agonists increase food intake while CB1 Receptor Antagonists reduce food intake. However, in some previous studies, tolerance to the anorectic effects of CB1 Antagonists develops within days. To further delineate the role of endogenous cannabinoid signaling in energy intake, we studied the effects of the CB1 antagonist AM 251 (1.25, 2.5 and 5 mg/kg ip), the anandamide membrane transporter inhibitor VDM 11 (10 mg/kg ip), and the CB1 agonists anandamide (1 mg/kg ip), and methanandamide (1 mg/kg ip), on food intake. A single administration of the CB1 antagonist AM 251 significantly reduced food intake for a total of 6 days (P<.05). Reductions in food intake brought about by AM 251 were accompanied by reductions in weight gain for 6 days (P<.05). Contrary to expectations, VDM 11 did not increase food intake in this study. Anandamide was also unable to increase food intake; however, the more stable agonist methanandamide significantly increased food intake 3 h after administration (P<.05). These results support the role of CB1 Receptor Antagonists in the treatment of obesity and suggest that the anorectic effect of AM 251 may last longer than previously reported.