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The effects of structural analogs of anandamide in rhesus monkeys discriminating Δ 9 ‐tetrahydrocannabinol (Δ 9 ‐THC)
Author(s) -
McMahon Lance Richard
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a410-d
Subject(s) - anandamide , cannabinoid receptor , cannabinoid , chemistry , pharmacology , endocannabinoid system , delta 9 tetrahydrocannabinol , tetrahydrocannabinol , antagonist , agonist , rimonabant , synthetic cannabinoids , receptor , biochemistry , biology
The endogenous cannabinoid anandamide and the plant‐derived cannabinoid Δ 9 ‐THC differ in their pharmacology, e.g., anandamide modulates a number of ion channels and has higher efficacy than Δ 9 ‐THC at cannabinoid CB 1 receptors. Modifying the chemical structure of anandamide has yielded compounds (R‐methanandamide) with greater metabolic stability than anandamide and others (arachidonylcyclopropylamide; ACPA) with greater selectivity for CB 1 relative to CB 2 receptors. The effects of Δ 9 ‐THC, ACPA, and R‐methanandamide were characterized, alone and in combination with the CB 1 antagonist SR 141716A, in rhesus monkeys discriminating Δ 9 ‐THC (0.1 mg/kg i.v.). ACPA and R‐methanandamide substituted for the Δ 9 ‐THC discriminative stimulus and were 6‐ and 18‐fold less potent, respectively, than Δ 9 ‐THC. SR 141716A (0.32 and 1 mg/kg) dose‐dependently antagonized the discriminative stimulus effects of Δ 9 ‐THC, and also antagonized the Δ 9 ‐THC‐like effects of ACPA and R‐methanandamide. Single‐dose apparent affinity analysis for SR 141716A (0.32 mg/kg) in combination with Δ 9 ‐THC, ACPA, and R‐methanandamide yielded pK B values of 6.7, 6.9, and 6.2, respectively. These results suggest that the same mechanism (e.g., CB 1 agonism) is responsible for the discriminative stimulus effects of Δ 9 ‐THC and structural analogs of anandamide. Supported by USPHS grants DA15468 and DA19222