Opioid Peptides--Molecular Mechanism Of Action

National Institute Of Environmental Health Sciences

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Abstract

The overall study encompassed research on two distinct families of opioids: (1) N-allyl-Dmt-derivatives of the endogenous endomorphins, originally isolated from mammalian brain, constitute a potent and highly specific mu-selective opioid tetrapeptide agonists; and (2) the effective dual delta-/mu-opioid receptor antagonist peptide, H-Dmt-Tic-Lys-NH-CH2-Ph (MZ-2). First, the N-allyl-Dmtendodomorphin-1 and -2 analogs exhibited neutral antagonism, suppressed morphine antinociception in vivo, eliminated morphine withdrawal symptoms, and importantly inhibited the ethanol-induced spontaneous IPSC in hippocampal neurons governed by the glutamate neurotransmission system involving GABA-A receptors. The observed effect of these mu-antagonists was two orders of magnitude greater than a FDA approved drug, a derivative of the morphinans, to combat alcoholism. The dual acting Dmt-Tic pharmacophore compound exhibited high delta-opioid receptor affinity (Ki <1 nM), while that for the mu-opioid receptor was very good (Ki approximately 4 nM);however, that activity depended on two structural factors: a non-charged C-terminus containing a hydrophobic group and the presence of a Lys residue, both of which are required for recognition by the mu-opioid receptor. Oral administration of MZ-2 exhibited potential human application in its ability in a mouse model of obesity (ob/ob mice) 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 these molecules could regulate or ameliorate alcoholism, obesity and osteoporosis. These unique molecules have therefore the potential for application to combat various human disease states which involve the neuronal reward mechanism in the brain: mu-opioid antagonists could be applicable in treatment of numerous disease states.