Many analogues and metabolites of delta8 and delta9-THC have been prepared in an effort to define and clarify structure activity relationships in the cannabinoids. Although many of the structural features responsible for the complex pharmacology of these compounds have been recognized, the detailed relationship between molecular structure and individual cannabinoid effects have not been identified. Also, no compound has been discovered which is a THC antagonist. The long-term objectives of this research are to identify those structural features responsible for individual cannabinoid effects and ultimately to elucidate the mechanism through which cannabinoids produce their distinctive behavioral effects. These objectives will be reached through a collaborative effort with Dr. B.R. Martin of the Medical College of Virginia.
The specific aims of the proposed research include the refinement of a new cannabinoid synthesis developed in the principal investigator's laboratory and the use of this protocol to prepare a variety of cannabinoid analogues and metabolites. The specific target molecules will be submitted for pharmacological evaluation using various behavioral models. Selected compounds will also be tested as possible THC antagonists. The synthetic sequence which will be employed and which has been used in a successful synthesis of 11-nor-9-carboxy THC has as a key step the reaction of a 1,3-dialkoxy-5-alkylaryllithium with apoverbenone, a readily available derivative of beta-pinene. Subsequent steps results in a completely regioselective, enantioselective and reasonably stereoselective approach to cannabinoids. Among the cannabinoid analogues to be prepared and submitted for behavioral evaluation are several derivatives of delta10-THC, 5'-11-dihydroxy-delta9- THC and derivatives of the 3-(1,1-dimethylheptyl) cannabinoids which are hydroxylated on the alkyl sidechain. Hydroxylated metabolites of CP55,940 and sidechain variations of delta8 and delta9-THC will also be prepared. Some polar cannabinoid analogues will be synthesized, including phosphate esters from several hydroxylated THC metabolites and analogues.
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|Chen, Jianhong; Smith, Valerie J; Huffman, John W (2010) 8-Chloro- and 5,8-Dichloro1-naphthoic Acids. Org Prep Proced Int 42:490-493|
|Huffman, John W; Hepburn, Seon A; Lyutenko, Nataliya et al. (2010) 1-Bromo-3-(1',1'-dimethylalkyl)-1-deoxy-?(8)-tetrahydrocannabinols: New selective ligands for the cannabinoid CB(2) receptor. Bioorg Med Chem 18:7809-15|
|Atwood, Brady K; Huffman, John; Straiker, Alex et al. (2010) JWH018, a common constituent of 'Spice' herbal blends, is a potent and efficacious cannabinoid CB receptor agonist. Br J Pharmacol 160:585-93|
|Huffman, John W; Hepburn, Seon A; Reggio, Patricia H et al. (2010) Synthesis and pharmacology of 1-methoxy analogs of CP-47,497. Bioorg Med Chem 18:5475-82|
|Vann, Robert E; Warner, Jonathan A; Bushell, Kristen et al. (2009) Discriminative stimulus properties of delta9-tetrahydrocannabinol (THC) in C57Bl/6J mice. Eur J Pharmacol 615:102-7|
|Huffman, John W; Thompson, Alicia L S; Wiley, Jenny L et al. (2008) Synthesis and pharmacology of 1-deoxy analogs of CP-47,497 and CP-55,940. Bioorg Med Chem 16:322-35|
|Poso, A; Huffman, J W (2008) Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands. Br J Pharmacol 153:335-46|
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