The overall purpose of the proposed studies is to compare the structure- activity relationships of the subjective effects of delta9- tetrahydrocannabinol (delta9-THC) and the endogenous cannabinoid receptor ligand anandamide. The SAR between chemical structure and drug action reveals the structural requirements for the stereoselectivity or stereospecificity of a given drug effect or drug action. Though some studies suggest that delta9-ThC and anandamide share many similar properties, a one-on-one relationship has not been demonstrated. Studies from our own and other laboratories have shown the ThC-like properties of synthetic cannabinoids and cannabimimetics are highly dependent on particular structural configurations. In general, these studies suggest that cannabimimetic activity is stereoselective, i.e., whether the compound is a (+ )- or (-)-enantiomer, methyl group planarity with regard to the cyclohexane ring, and characteristics of the side chain. The proposed studies investigate potential stereoselectivity of known cannabimimetic compounds with regard to anandamide. These studies also focus on identifying useful pharmacotherapies for cannabis abuse by effectively blocking the psychoactive, cannabimimetic properties. Though a number of compounds have been identified that have cannabimimetic properties, compounds that effectively block or antagonize the THC cue have not yet been isolated. The present project will primarily utilize drug discrimination procedures with rats as an animal model for assessing the psychoactive properties of delta9-ThC, anandamide, and related test compounds. Drug discrimination is the most commonly used paradigm for studying the subjective, intoxicating effects of drugs in preclinical psychopharmacology.
The Aims of this proposal will be addressed in a series of 4 main experiments, requiring 4 years to complete. The overall purpose is to: 1) determine if the SAR of delta9-THC and anadamide are similar with regard to subjective discriminative stimulus properties, and 2) explore the potential for antagonism of cannabimimetic effects. By providing important information on the SAR of endogenous anandamide and exogenous delta9-ThC, as well as potential cannabimimetic antagonists, these studies will not only add to our understanding of the behavioral neurobiology of cannabis abuse and dependence, but may also lead to the development of effective pharmacological treatments.

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National Institute on Drug Abuse (NIDA)
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Special Emphasis Panel (SRCD (27))
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Allegheny University of Health Sciences
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Järbe, Torbjörn U C; Raghav, Jimit Girish (2017) Tripping with Synthetic Cannabinoids (""Spice""): Anecdotal and Experimental Observations in Animals and Man. Curr Top Behav Neurosci 32:263-281
Järbe, Torbjörn U C; LeMay, Brian J; Thakur, Ganesh A et al. (2016) A high efficacy cannabinergic ligand (AM4054) used as a discriminative stimulus: Generalization to other adamantyl analogs and ?(9)-THC in rats. Pharmacol Biochem Behav 148:46-52
Järbe, Torbjörn U C; Gifford, Roger S; Zvonok, Alexander et al. (2016) [INCREMENT]9-Tetrahydrocannabinol discriminative stimulus effects of AM2201 and related aminoalkylindole analogs in rats. Behav Pharmacol 27:211-4
Nikas, Spyros P; Sharma, Rishi; Paronis, Carol A et al. (2015) Probing the carboxyester side chain in controlled deactivation (-)-?(8)-tetrahydrocannabinols. J Med Chem 58:665-81
Tai, Sherrica; Nikas, Spyros P; Shukla, Vidyanand G et al. (2015) Cannabinoid withdrawal in mice: inverse agonist vs neutral antagonist. Psychopharmacology (Berl) 232:2751-61
Järbe, Torbjörn U C; Gifford, Roger S (2014) ""Herbal incense"": designer drug blends as cannabimimetics and their assessment by drug discrimination and other in vivo bioassays. Life Sci 97:64-71
Sharma, Rishi; Nikas, Spyros P; Guo, Jason Jianxin et al. (2014) C-ring cannabinoid lactones: a novel cannabinergic chemotype. ACS Med Chem Lett 5:400-4
Järbe, Torbjörn U C; LeMay, Brian J; Halikhedkar, Aneetha et al. (2014) Differentiation between low- and high-efficacy CB1 receptor agonists using a drug discrimination protocol for rats. Psychopharmacology (Berl) 231:489-500
Sharma, Rishi; Nikas, Spyros P; Paronis, Carol A et al. (2013) Controlled-deactivation cannabinergic ligands. J Med Chem 56:10142-57
Järbe, Torbjörn U C; Tai, Sherrica; LeMay, Brian J et al. (2012) AM2389, a high-affinity, in vivo potent CB1-receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice. Psychopharmacology (Berl) 220:417-26

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