Cannabinoid agonists, such as delta9-tetrahydrocannabinol (delta9-THC), the major psychoactive component of marijuana, have been demonstrated to relieve pain, and to reduce chemotherapy-induced nausea and weight loss. Unfortunately, cannabinoid drugs also exhibit disturbing psychotomimetic side effects. Our goal is to develop cannabinoid Pharmaceuticals that retain the medically important pharmacological effects of delta9-THC, but produce fewer side effects. In the present proposal we plan to utilize a novel, highly sensitive experimental method, plasmon-waveguide resonance (PWR) spectroscopy to determine: a. whether structurally different classes of cannabinoid agonists stabilize unique cannabinoid receptor conformations; and, b. whether agonist-bound CB1 cannabinoid receptor conformations exhibit specificity for G protein alpha-subunits; and/or, c. G protein beta-gamma-subunits. We have already demonstrated that the PWR technique is a valuable tool to investigate agonist-mediated structural changes in G protein-coupled receptors, to measure the affinity of G protein types to the agonist-bound receptor conformations and to assess the ability of agonist-bound GPCRs to activate individual G protein types. Identification of cannabinoid drugs that exhibit selectivity for individual G protein types may provide the means to separate the medically useful effects of cannabinoids from their undesirable side effects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA018748-02
Application #
7127176
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Hillery, Paul
Project Start
2005-07-15
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$221,177
Indirect Cost
Name
University of Arizona
Department
Pharmacology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Georgieva, Teodora; Devanathan, Savitha; Stropova, Dagmar et al. (2008) Unique agonist-bound cannabinoid CB1 receptor conformations indicate agonist specificity in signaling. Eur J Pharmacol 581:19-29
Yue, Xu; Tumati, Suneeta; Navratilova, Edita et al. (2008) Sustained morphine treatment augments basal CGRP release from cultured primary sensory neurons in a Raf-1 dependent manner. Eur J Pharmacol 584:272-7