Opioid Peptides--Molecular Mechanism Of Action

National Institute Of Environmental Health Sciences

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Abstract

The overall studies encompassed research on two distinct family of opioid compounds, derivatives of the endogenous endomorphin family of highly specific mu-selective opioid peptides and the equallly potent delta-opioid receptor antagonist family of peptides, consisting of the general formula R-Dmt-Tic-R1-R2, investigated several pertinent factors on the bioactivity of these compounds. First, the endomorphins, N-allylDmt-1endodomorphin-1 and -2 became specific mu antagonists: exhibited neutral antagonism, suppressed morphine antinociception in vivo, eliminated morphine withdrawal symptoms completely, and inhibited the ethanol-induced spontaneous IPSC in hippocampal neurons. Modifications of the Dmt-Tic pharmacophore, included N-alkylation (R), linker length and composition (R), and the C-terminal composition of the compound (R), which included various fluorescent moieties. The Dmt-Tic pharmacophoric compounds exhibited high delta-opioid receptor affinities (Ki less than 0.1 nM), while high mu-opioid receptor affinities (Ki approximately or less than 1 nM) depended two factors: a non-charged C-terminus or the presence of a Lys residue, a large hydrophobic or aromatic group (Bid or Ph). The inherent delta antagonism was conversted to an agonist by altering the length of the linker (R1 = Gly, R2 = Bid) and reverted back to an antagonist substitution of Gly by Lys; however, Lys also formed a non-selective molecule with potent delta and mu antagonism. One fluorescent derivative had highly selectivity (greater than 4,000) for the delta-opioid receptor as a non-competitive or irreversible antagonist; data were submitted as an EIR for patent protection. Similarly an 18-F-labeled molecule only bound to systemic delta receptors, indicative of a potential role to reveal lung tumorlets non-invasively by PET scans, since these cancers express delta receptors in their surface membranes. The potential of these compounds lies in their ability to image lung tumors in vivo without invasive surgerical intervention and may be suitable for the early detection of lung cancer; a provision patent was filed. The data verified that Dmt is the key residue for all activity and slight modification of the molecules, be the Dmt-Tic pharmacophore or endomorphins provides significant changes in the bioactivity spectrum. These unique molecules have the potential for application to combat various human disease states: mu-opioid antagonists could be applicable in treatment of obesity and alcoholism, while delta-opoid agonists might alleviate chronic problems associated with asthma.