Abstract

Significance: Salvinorin A, a naturally occurring neoclaridane diterpine and the main active ingredient of the 'magic mint' hallucinogenic plant Salvia divinorum, is a potent and selective k-opioid receptor agonist (Roth et al., Proc Natl Acad Sci USA, 2002). Salvia divinorum and Salvinorin A thus represent a novel class of abused drugs (Sheffler and Roth, Trends Pharmacol Sci, in press) which selectively target the kappa-opioid receptor. The discovery that a diterpine is a selective peptide receptor agonist is unique and unprecedented. Therefore, the elucidation of the structural features responsible for Salvinorin A's actions at k-opioid receptors will illuminate novel approaches for peptide drug design. Investigation of the interaction of Salvinorin A with the k-opioid receptor may also provide a case study representing an innovative strategy for the design of drugs with exceptionally high selectivity. Thus, non-amine ligands, such as salvinorin A, have a potential for nearly absolute selectivity. To accomplish this overall goal we will test the following two hypotheses and 5 specific aims: Hypothesis #1: Salvinorin A interacts with the k-opioid receptor in a unique manner.
Specific aim #1 : To determine the structural features of the k-opioid receptor essential for binding Salvinorin A via a combination of site-directed mutagenesis and molecular modeling.
Specific aim #2 : To determine the structural features of the k-opioid receptor essential for the agonist actions of Salvinorin A at the KOR via a combination of site-directed mutagenesis and molecular modeling approaches.
Specific aim #3 : To compare the mode of binding and activation of the KOR by Salvinorin A with selected alkaloid agonists. Hypothesis #2: The 2-methoxycarbonyl position of Salvinorin A is essential for binding to and activation of the k-opioid receptor.
Specific aim #4 : To compare the binding and functional properties of a series of naturally occurring and synthetic 2-substituted Saivinorin A derivatives. These studies are likely to clarify how Salvinorin A and related drugs of abuse mediate their actions at the molecular and cellular levels and will lead to treatments for the side-effects related to Salvinorin A abuse.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA017204-01
Application #
6708199
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (02))
Program Officer
Hillery, Paul
Project Start
2003-09-30
Project End
2008-06-30
Budget Start
2003-09-30
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$356,000
Indirect Cost

  Institution

Name
Case Western Reserve University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106

  Publications

Che, Tao; Majumdar, Susruta; Zaidi, Saheem A et al. (2018) Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor. Cell 172:55-67.e15
Manglik, Aashish; Lin, Henry; Aryal, Dipendra K et al. (2016) Structure-based discovery of opioid analgesics with reduced side effects. Nature 537:185-190
Grace, Peter M; Strand, Keith A; Galer, Erika L et al. (2016) Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci U S A 113:E3441-50
Bruchas, Michael R; Roth, Bryan L (2016) New Technologies for Elucidating Opioid Receptor Function. Trends Pharmacol Sci 37:279-289
Roth, Bryan L (2016) DREADDs for Neuroscientists. Neuron 89:683-94
Salaga, M; Polepally, P R; Zielinska, M et al. (2015) Salvinorin A analogues PR-37 and PR-38 attenuate compound 48/80-induced itch responses in mice. Br J Pharmacol 172:4331-41
Vardy, Eyal; Sassano, Maria F; Rennekamp, Andrew J et al. (2015) Single Amino Acid Variation Underlies Species-Specific Sensitivity to Amphibian Skin-Derived Opioid-like Peptides. Chem Biol 22:764-75
Robinson, J Elliott; Vardy, Eyal; DiBerto, Jeffrey F et al. (2015) Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism. Neuropsychopharmacology 40:2614-22
Huang, Xi-Ping; Karpiak, Joel; Kroeze, Wesley K et al. (2015) Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65. Nature 527:477-83
Vardy, Eyal; Robinson, J Elliott; Li, Chia et al. (2015) A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior. Neuron 86:936-946

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