Food intake inhibition and reduction in body weight gain in lean and obese rodents treated with GW438014A, a potent and selective NPY-Y5 receptor antagonist
Numerous reports have implicated theY5 receptor as the ‘feeding’ receptor mediating the orexigenic action of neuropeptide Y (NPY). This notion is supported by the correlation between the in vitro functional and binding activities of different peptide agonists and their potent stimulation of food int...
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| Veröffentlicht in: | Regulatory peptides 2002-06, Vol.106 (1), p.47-54 |
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| creator | Daniels, A.J. Grizzle, M.K. Wiard, R.P. Matthews, J.E. Heyer, D. |
| description | Numerous reports have implicated theY5 receptor as the ‘feeding’ receptor mediating the orexigenic action of neuropeptide Y (NPY). This notion is supported by the correlation between the in vitro functional and binding activities of different peptide agonists and their potent stimulation of food intake in rodents. We have discovered a series of small molecule heterocycles with high affinity, selectivity, and functional antagonism for Y5 receptors. Intraperitoneal (i.p.) administration of GW438014A into rodents, resulted in a potent reduction of NPY-induced and normal overnight food intake. Brain levels of GW438014A were detected well in excess of its binding IC
50 for up to 3 h post-dosing. Daily (i.p., BID, 10 mg/kg) administration of this compound to Zucker Fatty rats for a period of 4 days resulted in a marked decrease in the rate of weight gain and a reduction in fat mass. No effect on food intake was observed following oral administration of GW438014A (25–100 mg/kg), consistent with the poor oral bioavailability ( |
| doi_str_mv | 10.1016/S0167-0115(02)00034-4 |
| format | Article |
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50 for up to 3 h post-dosing. Daily (i.p., BID, 10 mg/kg) administration of this compound to Zucker Fatty rats for a period of 4 days resulted in a marked decrease in the rate of weight gain and a reduction in fat mass. No effect on food intake was observed following oral administration of GW438014A (25–100 mg/kg), consistent with the poor oral bioavailability (<3%) and low brain levels observed.</description><identifier>ISSN: 0167-0115</identifier><identifier>EISSN: 1873-1686</identifier><identifier>DOI: 10.1016/S0167-0115(02)00034-4</identifier><identifier>PMID: 12047910</identifier><identifier>CODEN: REPPDY</identifier><language>eng</language><publisher>Shannon: Elsevier B.V</publisher><subject>Adipose Tissue - drug effects ; Administration, Oral ; Animals ; Benzimidazoles - pharmacology ; Biological and medical sciences ; Feeding behavior ; Feeding Behavior - drug effects ; Hypothalamus ; Male ; Medical sciences ; Metabolic diseases ; Molecular Structure ; Obesity ; Obesity - physiopathology ; Rats ; Rats, Sprague-Dawley ; Rats, Zucker ; Receptor binding ; Receptors, Neuropeptide Y - antagonists & inhibitors ; Thinness - metabolism ; Weight Gain - drug effects</subject><ispartof>Regulatory peptides, 2002-06, Vol.106 (1), p.47-54</ispartof><rights>2002 Elsevier Science B.V.</rights><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c391t-8e470b8cf559cf5e3d565210e2701f55d1ebb5016aedcaba0810806647599b4e3</citedby><cites>FETCH-LOGICAL-c391t-8e470b8cf559cf5e3d565210e2701f55d1ebb5016aedcaba0810806647599b4e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0167-0115(02)00034-4$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,782,786,3554,27933,27934,46004</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13725617$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12047910$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Daniels, A.J.</creatorcontrib><creatorcontrib>Grizzle, M.K.</creatorcontrib><creatorcontrib>Wiard, R.P.</creatorcontrib><creatorcontrib>Matthews, J.E.</creatorcontrib><creatorcontrib>Heyer, D.</creatorcontrib><title>Food intake inhibition and reduction in body weight gain in lean and obese rodents treated with GW438014A, a potent and selective NPY-Y5 receptor antagonist</title><title>Regulatory peptides</title><addtitle>Regul Pept</addtitle><description>Numerous reports have implicated theY5 receptor as the ‘feeding’ receptor mediating the orexigenic action of neuropeptide Y (NPY). This notion is supported by the correlation between the in vitro functional and binding activities of different peptide agonists and their potent stimulation of food intake in rodents. We have discovered a series of small molecule heterocycles with high affinity, selectivity, and functional antagonism for Y5 receptors. Intraperitoneal (i.p.) administration of GW438014A into rodents, resulted in a potent reduction of NPY-induced and normal overnight food intake. Brain levels of GW438014A were detected well in excess of its binding IC
50 for up to 3 h post-dosing. Daily (i.p., BID, 10 mg/kg) administration of this compound to Zucker Fatty rats for a period of 4 days resulted in a marked decrease in the rate of weight gain and a reduction in fat mass. No effect on food intake was observed following oral administration of GW438014A (25–100 mg/kg), consistent with the poor oral bioavailability (<3%) and low brain levels observed.</description><subject>Adipose Tissue - drug effects</subject><subject>Administration, Oral</subject><subject>Animals</subject><subject>Benzimidazoles - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Feeding behavior</subject><subject>Feeding Behavior - drug effects</subject><subject>Hypothalamus</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metabolic diseases</subject><subject>Molecular Structure</subject><subject>Obesity</subject><subject>Obesity - physiopathology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Rats, Zucker</subject><subject>Receptor binding</subject><subject>Receptors, Neuropeptide Y - antagonists & inhibitors</subject><subject>Thinness - metabolism</subject><subject>Weight Gain - drug effects</subject><issn>0167-0115</issn><issn>1873-1686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9u1DAQxi0EokvhEUC-gEAiMJPEsXNCVUULUgVIgFBPlmPP7hqy8WJ7W_VdeFjc7IoeuczI49_80fcx9hThDQJ2b7-WICtAFC-hfgUATVu199gClWwq7FR3ny3-IUfsUUo_AVBI2TxkR1hDK3uEBftzFoLjfsrmF5W09oPPPkzcTI5Hcjs7v_zEh-Bu-DX51TrzlfFzbSSzJ8NAiXgMjqaceI5kMjl-7fOan_9oGwXYnrzmhm9DLsTckmikMvyK-Kcvl9WlKNssbXOI5TebVZh8yo_Zg6UZEz055GP2_ez9t9MP1cXn84-nJxeVbXrMlaJWwqDsUoi-BGqc6ESNQLUELEWHNAyiiGHIWTMYUAgKuq6Vou-Hlppj9mI_dxvD7x2lrDc-WRpHM1HYJS1RKqXqroBiD9oYUoq01NvoNybeaAR9a4uebdG3mmuo9WyLbkvfs8OC3bAhd9d18KEAzw-ASdaMy2gm69Md18hadCgL927PUZHjylPUyXqaLDlf9MvaBf-fU_4CFRKpfg</recordid><startdate>20020615</startdate><enddate>20020615</enddate><creator>Daniels, A.J.</creator><creator>Grizzle, M.K.</creator><creator>Wiard, R.P.</creator><creator>Matthews, J.E.</creator><creator>Heyer, D.</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20020615</creationdate><title>Food intake inhibition and reduction in body weight gain in lean and obese rodents treated with GW438014A, a potent and selective NPY-Y5 receptor antagonist</title><author>Daniels, A.J. ; Grizzle, M.K. ; Wiard, R.P. ; Matthews, J.E. ; Heyer, D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c391t-8e470b8cf559cf5e3d565210e2701f55d1ebb5016aedcaba0810806647599b4e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Adipose Tissue - drug effects</topic><topic>Administration, Oral</topic><topic>Animals</topic><topic>Benzimidazoles - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Feeding behavior</topic><topic>Feeding Behavior - drug effects</topic><topic>Hypothalamus</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metabolic diseases</topic><topic>Molecular Structure</topic><topic>Obesity</topic><topic>Obesity - physiopathology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Rats, Zucker</topic><topic>Receptor binding</topic><topic>Receptors, Neuropeptide Y - antagonists & inhibitors</topic><topic>Thinness - metabolism</topic><topic>Weight Gain - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Daniels, A.J.</creatorcontrib><creatorcontrib>Grizzle, M.K.</creatorcontrib><creatorcontrib>Wiard, R.P.</creatorcontrib><creatorcontrib>Matthews, J.E.</creatorcontrib><creatorcontrib>Heyer, D.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Regulatory peptides</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Daniels, A.J.</au><au>Grizzle, M.K.</au><au>Wiard, R.P.</au><au>Matthews, J.E.</au><au>Heyer, D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Food intake inhibition and reduction in body weight gain in lean and obese rodents treated with GW438014A, a potent and selective NPY-Y5 receptor antagonist</atitle><jtitle>Regulatory peptides</jtitle><addtitle>Regul Pept</addtitle><date>2002-06-15</date><risdate>2002</risdate><volume>106</volume><issue>1</issue><spage>47</spage><epage>54</epage><pages>47-54</pages><issn>0167-0115</issn><eissn>1873-1686</eissn><coden>REPPDY</coden><abstract>Numerous reports have implicated theY5 receptor as the ‘feeding’ receptor mediating the orexigenic action of neuropeptide Y (NPY). This notion is supported by the correlation between the in vitro functional and binding activities of different peptide agonists and their potent stimulation of food intake in rodents. We have discovered a series of small molecule heterocycles with high affinity, selectivity, and functional antagonism for Y5 receptors. Intraperitoneal (i.p.) administration of GW438014A into rodents, resulted in a potent reduction of NPY-induced and normal overnight food intake. Brain levels of GW438014A were detected well in excess of its binding IC
50 for up to 3 h post-dosing. Daily (i.p., BID, 10 mg/kg) administration of this compound to Zucker Fatty rats for a period of 4 days resulted in a marked decrease in the rate of weight gain and a reduction in fat mass. No effect on food intake was observed following oral administration of GW438014A (25–100 mg/kg), consistent with the poor oral bioavailability (<3%) and low brain levels observed.</abstract><cop>Shannon</cop><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>12047910</pmid><doi>10.1016/S0167-0115(02)00034-4</doi><tpages>8</tpages></addata></record> |
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| subjects | Adipose Tissue - drug effects Administration, Oral Animals Benzimidazoles - pharmacology Biological and medical sciences Feeding behavior Feeding Behavior - drug effects Hypothalamus Male Medical sciences Metabolic diseases Molecular Structure Obesity Obesity - physiopathology Rats Rats, Sprague-Dawley Rats, Zucker Receptor binding Receptors, Neuropeptide Y - antagonists & inhibitors Thinness - metabolism Weight Gain - drug effects |
| title | Food intake inhibition and reduction in body weight gain in lean and obese rodents treated with GW438014A, a potent and selective NPY-Y5 receptor antagonist |
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