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In order to explore the structural requirements for cannabinoid activity we have been involved in the design and synthesis of stereochemically defined high affinity probes for the cannabinoid receptor. This effort has involved the development of irreversible ligands which will allow us to obtain detailed information on the cannabinoid receptor active site(s). The irreversible ligands, which incorporate highly reactive functional groups in a strategic position of the ligand, may form covalent bonds with amino acid residues at the receptor active site or in the neighborhood of this site. We shall discuss the biochemical properties of one of these probes, which incorporates the electrophilic isothiocyanate group into the structure of the highly potent cannabinoid agonist (-)-1',1'-dimethylheptyl-delta 8-THC. This ligand, (-)-7'-isothiocyanato-1',1'-dimethylheptyl-delta 8-THC (7'-NCS-DMH-delta 8-THC), was evaluated for its affinity for cannabinoid binding sites using rat forebrain membrane preparations and found to have an apparent IC50 value of 660 pM. Incubation of the membrane preparation with a ligand concentration of five times the apparent IC50 resulted in the irreversible occupation of nearly all of the receptor specific binding sites.

Citation

K L Morse, D J Fournier, X Li, J Grzybowska, A Makriyannis. A novel electrophilic high affinity irreversible probe for the cannabinoid receptor. Life sciences. 1995;56(23-24):1957-62

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PMID: 7776819

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