Dynorphins are a family of opioid peptides derived from a single precursor and known to have a wide profile of pharmacological actions. Since the pharmakinetics vary with peptide size, the catabolism of dynorphin A (the most active kappa-selective fragment) will be emphasized to determine the nature of enzyme(s) present in different brain fractions (SPM, Golgi fractions, etc.) responsible for C-terminal shortening, and hence alteration of the address signals directed towards the different opioid receptor types. To confirm observations made in preliminary studies with brain fractions, a number of key C- terminally active enzymes will be purified and used in a coordinate manner to demonstrate production of active dynorphin intermedicates. Such enzymes will include one or more membrane bound carboxypeptidases active at pH 5-6.5, angiotension coverting enzyme, cysteine proteinases with peptidyl dipeptidase actions (cathepsin B), and prolyl endopeptidase. With the aim of developing new classes of inhibitor active in vivo, a number of known synthetic compounds will be compared to ones recently synthesized in the laboratory, or purified from brain fractions themselves. Such materials will include a new class of potent cysteine proteinase inhibitors shown to suppress conversion of prodynorphins or proenkephalins.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA004178-02
Application #
3209443
Study Section
Pharmacology I Research Subcommittee (DABR)
Project Start
1987-05-01
Project End
1990-04-30
Budget Start
1988-05-01
Budget End
1989-04-30
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962