Opioid Peptides--Molecular Mechanism Of Action

National Institute Of Environmental Health Sciences

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Abstract

The overall study encompassed research on an effective dual mu-/delta-opioid receptor antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph (MZ-2). The dual acting Dmt-Tic pharmacophoric compound exhibited high opioid receptor affinity (Ki delta <1 nM, Ki mu 4 nM). The non-charged C-terminus containing a hydrophobic group and the presence of a Lys residue are required for recognition by the mu-opioid receptor. Oral administration of MZ-2 in a mouse model of obesity (ob/ob mine) and diet-induced obesity in mice containing a time-released Azlet mini-pumps to continually supply the drug in order to reduce body weight gain, increase nocturnal activity in both obese and lean mice, enhance bone mineral deposition and produce positive effects on serum hormones and glucose levels. The data verify that this drug, MZ-2, could ameliorate various factors contributing to obesity and alleviate symptoms of osteoporosis by enhancing bone mineral deposition by 30%. This unique molecule has the potential application to combat human disease states involving the neuronal reward mechanism in the brain: dual mu-/delta-opioid antagonists could be applicable in treatment of numerous disease states.