Methionine and leucine enkephalins, endogenous opiate-like compounds, may be important in understanding both drug and alcohol addiction. They, along with other peptides, have been posulated to be natural regulators of analgesia and euphoria. In addition, they seem to be vital factors in determining desire for alcohol. Knowing how enkephalins bind to opiate receptors, i.e., which atoms and/or hydrophobic groups are necessary to interact with receptor atoms, would facilitate the conception and synthesis of new compounds with these same binding features. We have determined the three-dimensional structure of leucine enkephalin in a highly solvated physiological-like environment. We will now undertake the elucidation of the crystal and molecular structures of a number of modified enkephalin analogues. Their three-dimensional stereochemistries will be compared with each other, with leucine-enkephalin, and with a number of opiates, opiate agonists and antagonists. Conclusions as to which stereochemical features of the enkephalins are necessary for these compounds to bind to opiate Mu and Delta receptors are expected to provide the basis for the design of new potentially non-addictive opiate agonists for the treatment of drug and alcohol addiction.
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