Delta9-Tetrahydrocannabinol (THC) is the primary CNS-active component of marijuana or hashish (Cannabis sativa). Potent tricyclic and bicyclic cannabinoid analogs developed at Pfizer Central Research were utilized to elucidate a cellular mechanism of action for delta9-THC. We determined that cannabimimetic compounds interact with a cannabinoid receptor on neuronal cells which regulates the cyclic AMP second messenger system. We developed a radioligand binding assay using the potent bicyclic cannabinoid agonist [3H]CP-55940, and have used it to biochemically and pharmacologically characterize the cannabinoid receptor. The goal of this project is to study cannabinoid receptor-ligand interactions at the cellular and molecular levels. This work will continue through the following specific aims to: 1.Continue characterization of novel affinity ligands and positron emission tomography (PET) scanning ligands; 2.Identify a cannabinoid-like binding activity present in the CNS, and characterize and purify the factor(s) responsible for this activity; and 3.Develop an immunoassay for the cannabinoid-like binding factor(s). It is expected that the determination and characterization of an endogenous cannabinoid-like binding factor(s) for the cannabinoid receptor will allow the development of new structure-activity relationship studies based on this novel molecule. This knowledge could lead to the development of potentially useful antagonists for the cannabinoid receptor. In addition, receptor subtypes for the endogenous cannabinoid-like binding factor could be sought. These studies will advance our understanding of the role of cannabinoceptive neurons in analgesia, cognition and memory, and motor behaviors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA006312-04
Application #
3212976
Study Section
Special Emphasis Panel (SRCD (10))
Project Start
1989-09-30
Project End
1995-07-31
Budget Start
1992-08-15
Budget End
1993-07-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Grace, Christy R R; Cowsik, Sudha M; Shim, Joong-Youn et al. (2007) Unique helical conformation of the fourth cytoplasmic loop of the CB1 cannabinoid receptor in a negatively charged environment. J Struct Biol 159:359-68
Mukhopadhyay, Somnath; Das, Sucharita; Williams, Evelyn A et al. (2006) Lipopolysaccharide and cyclic AMP regulation of CB(2) cannabinoid receptor levels in rat brain and mouse RAW 264.7 macrophages. J Neuroimmunol 181:82-92
Shim, Joong-Youn; Howlett, Allyn C (2006) WIN55212-2 docking to the CB1 cannabinoid receptor and multiple pathways for conformational induction. J Chem Inf Model 46:1286-300
Mukhopadhyay, Somnath; Howlett, Allyn C (2005) Chemically distinct ligands promote differential CB1 cannabinoid receptor-Gi protein interactions. Mol Pharmacol 67:2016-24
Shim, Joong-Youn; Howlett, Allyn C (2004) Steric trigger as a mechanism for CB1 cannabinoid receptor activation. J Chem Inf Comput Sci 44:1466-76
Shim, Joong-Youn; Welsh, William J; Howlett, Allyn C (2003) Homology model of the CB1 cannabinoid receptor: sites critical for nonclassical cannabinoid agonist interaction. Biopolymers 71:169-89
Shim, Joong-Youn; Welsh, William J; Cartier, Etienne et al. (2002) Molecular interaction of the antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1- (2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide with the CB1 cannabinoid receptor. J Med Chem 45:1447-59
Mukhopadhyay, Somnath; Shim, Joong-Youn; Assi, Abdel-Azim et al. (2002) CB(1) cannabinoid receptor-G protein association: a possible mechanism for differential signaling. Chem Phys Lipids 121:91-109
Meschler, J P; Kraichely, D M; Wilken, G H et al. (2000) Inverse agonist properties of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A) and 1-(2-chlorophenyl)-4-cyano-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxyl ic acid phenylamide (CP-272871) for th Biochem Pharmacol 60:1315-23
Howlett, A C; Wilken, G H; Pigg, J J et al. (2000) Azido- and isothiocyanato-substituted aryl pyrazoles bind covalently to the CB1 cannabinoid receptor and impair signal transduction. J Neurochem 74:2174-81

Showing the most recent 10 out of 26 publications