Given the potential pharmacological and physiological diversity arising from heterodimerization of opioid receptors, an important challenge in opioid research is the development of selective tools for the investigation of such phenotypic opioid receptors. Selective pharmacological tools that can span the divide between cultured cells and in vivo systems would clarify the functional roles and localization of heterodimeric opioid receptors in experimental animals. Thus, the broad, long-term objectives of this research are to develop ligands with selectivity for heterodimeric opioid receptors as tools to study the functional roles of physically associated opioid receptors in the central nervous system. The long-term goal is to use the information obtained from such studies to develop superior analgesics that are devoid of tolerance and dependence.
The specific aims of the present application include the synthesis and biological evaluation of ligands that are selective for opioid receptor heterodimers. Based on reports of heterodimeric opioid receptors in cultured cells and on the large body of literature that implicates interaction between mu and kappa opioid receptors and mu and NK1, CCK2, ORL1, and CB1 receptors in vivo, a total of ten series of compounds will be synthesized. Eight of the proposed series are bivalent ligands that will include mu and kappa opioid pharmacophores or a mu agonist pharmacophore combined with NK1, CCK2, ORL1, or CB1 antagonist pharmacophores. The pharmacophores in each of these bivalent series will be linked to each other through spacers containing 12-22 atoms. The antagonist non-opioid pharmacophores were selected because interaction between mu opioid receptors and the above receptors have been reported to modulate antinociception, tolerance and/or dependence. The corresponding series of monovalent ligands with matching spacers and matching pharmacophores will be synthesized as controls. There will be 11 compounds in each of these 16 series. The remaining two series will be structurally related to 6'-GNTI which has been reported to produce analgesia in mice by selectively targeting spinal delta-kappa opioid receptor heterodimers. Because analgesia of 6'-GNTI is mediated spinally, such compounds should not possess the supraspinal side-effects generally associated with clinically employed analgesics. As a second approach to development of spinally-selective analgesics, the Pl/s library of ~1000 opiates will undergo Flexstation screening on cultured cells containing coexpressed and singly expressed delta and kappa opioid receptors. Target compounds and screening hits will be tested in cultured cells and in behavioral tests in mice that include evaluation of tolerance and physical dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA001533-35
Application #
7821194
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (91))
Program Officer
Hillery, Paul
Project Start
1981-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
35
Fiscal Year
2010
Total Cost
$608,773
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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
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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
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

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