Abstract

Pentapeptide enkephalin analogues that possess delta opioid antagonist activity will be modified with a variety of electrophilic substitutents at the Phe4 residue in order to develop ligands that selectively or specifically block delta receptors in a nonequilibrium fashion. These ligands will be tested in vitro on the mouse vas deferens and guinea pig ileum preparations in order to evaluate the selectivity and nonequilibrium nature of the effect. Receptor binding studies will be conducted to obtain additional support for covalent bonding to delta sites. In order to evaluate and refine a model for morphine tolerance, the binding of the mu-specific nonequilibrium antagonist, [3H]Beta-FNA, to brain slices from naive and tolerant mice will be investigated.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA001533-10
Application #
3206946
Study Section
(DABB)
Project Start
1981-06-01
Project End
1989-05-31
Budget Start
1985-06-01
Budget End
1986-05-31
Support Year
10
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
University of Minnesota Twin Cities
Department
Type
Schools of Pharmacy
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455

  Publications

Le Naour, Morgan; Akgün, Eyup; Yekkirala, Ajay et al. (2013) Bivalent ligands that target ? opioid (MOP) and cannabinoid1 (CB1) receptors are potent analgesics devoid of tolerance. J Med Chem 56:5505-13
Yekkirala, Ajay S; Kalyuzhny, Alexander E; Portoghese, Philip S (2013) An immunocytochemical-derived correlate for evaluating the bridging of heteromeric mu-delta opioid protomers by bivalent ligands. ACS Chem Biol 8:1412-6
Le Naour, Morgan; Lunzer, Mary M; Powers, Mike D et al. (2012) Opioid activity of spinally selective analogues of N-naphthoyl-ýý-naltrexamine in HEK-293 cells and mice. J Med Chem 55:670-7
Berg, Kelly A; Rowan, Matthew P; Gupta, Achla et al. (2012) Allosteric interactions between ýý and ýý opioid receptors in peripheral sensory neurons. Mol Pharmacol 81:264-72
Wise, Laura E; Premaratne, Ishani D; Gamage, Thomas F et al. (2012) l-theanine attenuates abstinence signs in morphine-dependent rhesus monkeys and elicits anxiolytic-like activity in mice. Pharmacol Biochem Behav 103:245-52
Metcalf, Matthew D; Yekkirala, Ajay S; Powers, Michael D et al. (2012) The ? opioid receptor agonist SNC80 selectively activates heteromeric ?-? opioid receptors. ACS Chem Neurosci 3:505-9
Yekkirala, Ajay S; Banks, Matthew L; Lunzer, Mary M et al. (2012) Clinically employed opioid analgesics produce antinociception via ?-? opioid receptor heteromers in Rhesus monkeys. ACS Chem Neurosci 3:720-7
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

Showing the most recent 10 out of 29 publications