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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003532-04
Application #
3208025
Study Section
(DABB)
Project Start
1984-06-01
Project End
1988-12-31
Budget Start
1987-07-01
Budget End
1988-12-31
Support Year
4
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Camerman, A; Mastropaolo, D; Camerman, N (1987) Azidothymidine: crystal structure and possible functional role of the azido group. Proc Natl Acad Sci U S A 84:8239-42
Mastropaolo, D; Camerman, A; Ma, L Y et al. (1987) Crystal structure of an extended-conformation leucine-enkephalin dimer monohydrate. Life Sci 40:1995-9
Mastropaolo, D; Camerman, A; Camerman, N (1986) Crystal structure of methionine-enkephalin. Biochem Biophys Res Commun 134:698-703
Camerman, A; Camerman, N (1986) Conformational features of the opioid peptides in the solid state: a review of X-ray crystallographic research. NIDA Res Monogr 69:351-63