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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Dual µ-/δ-Opioid Antagonist, H-Dmt-Tic-Lys-NH-CH 2 -Ph:Potential Candidate for Management of Obesity,Diabetes and OsteoporosisLawrence H. Lazarus 1 , Gianfranco Balboni 2 , Severo Salvadori 3 , andEwa D. Marczak 11 National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709,U.S.A., 2 Department of Toxicology and Pharmacology, University of Cagliari, Cagliari,I-09124, Italy, 3 Department of Pharmaceutical Science and Biotechnology Center,University of Ferrara, Ferrara, I-44100, ItalyIntroductionOpioid antagonists represent an important class of synthetic drugs affecting neural rewardandhomeostatic mechanisms. Reward mechanisms include craving, addiction andcompulsive behaviors, such as excessive consumption of high caloric foods leading toobesity, and entail interaction with the μ-opioid receptor [1]. The potential amelioration ofobesity by selective opioid antagonists could be a relevant approach to curtail these majorpublic health issues. Whereas obesity exerts an economic toll and severe medical and socialconsequences, prevention remains limited; many treatments are merely palliative and ratesof recidivism are high. While osteoporosis affects >90% of postmenopausal womenworldwide, patients taking anti-pain medication, particularly opiate-derivatives, havesymptoms of osteoporosis and exhibit increased risk of bone fractures due to loss of bonemass [2,3]. This effect is related to a direct interaction of opioid agonists on osteoblasts toregulate bone mineral density (BMD). Therefore, an opioid antagonist that has the potentialto simultaneously enhance osteoporosis and treat obesity exists.We described the synthesis and pharmacological profile of a potent dual actingµ-/δ-antagonist (MZ-2, Figure 1) [4] that inhibited morphine antinociception, developmentof morphine tolerance [5], and decreased obese-related factors in ob/ob mice [6] and dietinducedobesity (DIO) mice [7]. MZ-2 portends to be a potential clinical candidate formanagement of obesity and related diseases, and the amelioration of osteoporosis.Results and DiscussionGenetically obese mice (ob/ob) and wt lean controls were treated daily for 3 weeks withMZ-2 (po, 10 mg/kg), followed by recovery for 2 weeks; control groups consisting of ob/oband wt animals received saline [6]. DIO mice were fed a high fat diet for 32 weeks beforetreating with saline or MZ-2 (10mg/kg/day via implanted mini-pumps) for 12 weeks [7].During treatment, mice were kept in either sedentary or with access to exercise wheels.Voluntary exercise was recorded for the duration of the experiment by magnetic switchesconnected to the Vital View 3000 data acquisition system (Mini Mitter, Bend, OR, U.S.A.).Bone mineral density (BMD) and body fat content were assessed before treatment and atthe end of experiment using PIXImus2 Mouse Densitometer (GE Medical Systems,Madison, WI, U.S.A.).8.0Weight gain (g)6.04.02.0SalineMZ-2Fig. 1. Structure of MZ-2.0.00 2 4 6 8 10 12Time (weeks)Fig. 2. Effect of MZ-2 or saline on body weightgain in sedentary DIO mice.316