The long term objective of this project is to create highly selective nonpeptide opioid receptor antagonists as pharmacological and biochemical probes to: a) sort out opioid receptor types and subtypes, b) investigate opioid receptor-mediated actions of endogenous and exogenous opioid ligands, and c) uncover potential clinical applications of such opioid antagonists. The design rationale involves modification of naltrexone with a key """"""""address: element to confer selectivity for an opioid receptor type or subtype. The address moiety will be attached to the naltrexone morphinan system through spacers that have different flexibilities and orientations in an effort to evaluate the relationship of the mobility and conformation of the address moiety and ligand selectivity. These studies will include ligands that are delta- and kappa-selective antagonists. Computer-aided molecular modeling will be carried out in an effort to determine whether or not the key elements in the selective nonpeptides occupy the same conformational space as selective opioid peptides. An approach to the design of novel mixed agonist-antagonist ligands will be undertaken as an approach to the design of potent analgesics. Three series of nonequilibrium antagonists will be synthesized and evaluated for selectivity at delta and kappa receptor subtypes. These ligands are based either on naltrindole (NTI) or in its benzofuran analogue (NTB). The delta-selective antagonists will contain electrophilic groups on the indole, benzofuran moiety, or on a N-benzyl substituent. The kappa- selective nonequilibrium antagonists contain a basic moiety attached through a methylene group to the 5' position of the indole system, with electrophilic groups attached to an N-benzyl substituent. Collaborative studies will be carried out with NTI and NTB to study their ability to suppress ethanol and cocaine uptake.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA001533-17
Application #
3206945
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1981-06-01
Project End
1997-05-31
Budget Start
1992-06-01
Budget End
1993-05-31
Support Year
17
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Pharmacy
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Aceto, Mario D; Harris, Louis S; Negus, S Stevens et al. (2012) MDAN-21: A Bivalent Opioid Ligand Containing mu-Agonist and Delta-Antagonist Pharmacophores and Its Effects in Rhesus Monkeys. Int J Med Chem 2012:327257
Yekkirala, Ajay S; Lunzer, Mary M; McCurdy, Christopher R et al. (2011) N-naphthoyl-beta-naltrexamine (NNTA), a highly selective and potent activator of ýý/kappa-opioid heteromers. Proc Natl Acad Sci U S A 108:5098-103
Ansonoff, Michael A; Portoghese, Philip S; Pintar, John E (2010) Consequences of opioid receptor mutation on actions of univalent and bivalent kappa and delta ligands. Psychopharmacology (Berl) 210:161-8

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