The long-term objective of this project is to develop electrophilic and photoaffinity ligands for opioid receptors which may be useful in the characterization and/or purification of these receptors. In addition, the compounds may provide long-acting agonists or antagonists. Electrophilic and photoactivatable groups are attached to ligands known to be bound to mu-, kappa-, or delta-opioid receptor subtypes. The compounds would be employed principally as pharmacological tools to aid in characterization of receptor subtypes. The compounds to be prepared are: 1. mu-Antagonists and agonists derived primarily from naltrexone, and less from oxymorphone, in which the electrophilic groups and photoaffinity probes are attached to the 6-, 7-, 8-positions. The major focus of this application is on mu-opioid receptor ligands. 2. Possible electrophilic and photoaffinity probes derived from the selective delta-antagonist naltrindole. 3. Possible electrophilic and photoaffinity probes of selective kappa- antagonist norbinaltorphimine and kappa-agonist ICI-199441. All compounds will be tested in opioid receptor binding assays for selectivity at mu-, kappa-, and delta-subclasses of opioid receptors. Active compounds with high affinity will also be tested for possible irreversible effects. Electrophiles will be preincubated and possible photoaffinity probes will be also be photolyzed. The binding assay will be repeated to determine is there is irreversible binding. Compounds with interesting activities will also be submitted to CPDD for testing in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA006675-03
Application #
3213366
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Pharmacy
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Palmer, R B; Upthagrove, A L; Nelson, W L (1997) (E)- and (Z)-7-arylidenenaltrexones: synthesis and opioid receptor radioligand displacement assays. J Med Chem 40:749-53
Chen, C; Yin, J; Li, J G et al. (1997) Irreversible binding of N-methyl-N-[(1S)-1-(4-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl-3,4 -dichlorophenylacetamide to the cloned rat kappa opioid receptor. Life Sci 61:787-94
Davis, R D; Nelson, W L (1995) Isothiocyanate-substituted benzyl ether opioid receptor ligands derived from 6 beta-naltrexol. J Med Chem 38:570-9
Nelson, T D; Davis, R D; Nelson, W L (1994) Synthesis and opioid receptor affinity of a series of aralkyl ethers of 6 alpha- and 6 beta-naltrexol. J Med Chem 37:4270-7
Weerawarna, S A; Davis, R D; Nelson, W L (1994) Isothiocyanate-substituted kappa-selective opioid receptor ligands derived from N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl] phenylacetamide. J Med Chem 37:2856-64
Klein, P; Nelson, W L (1992) O3-(2-carbomethoxyallyl) ethers of opioid ligands derived from oxymorphone, naltrexone, etorphine, diprenorphine, norbinaltorphimine, and naltrindole. Unexpected O3-dealkylation in the opioid radioligand displacement assay. J Med Chem 35:4589-94
Dasher, W E; Klein, P; Nelson, W L (1992) Electrophilic opioid ligands. Oxygen tethered alpha-methylene-gamma-lactone, acrylate, isothiocyanate, and epoxide derivatives of 6 beta-naltrexol. J Med Chem 35:2374-84
Klein, P; Nelson, W L (1991) Electrophilic gamma-lactone kappa-opioid receptor probes. Analogues of 2'-hydroxy-2-tetrahydrofurfuryl-5,9-dimethyl-6,7-benzomorphan diastereomers. J Med Chem 34:2438-44