Synthesis of Covalent Probes for the Radiolabeling of the Cannabinoid Receptor

• Published in: Journal of organic chemistry Vol. 68; no. 1; pp. 55 - 61
• Main Authors: Chu, Chester, Ramamurthy, Arun, Makriyannis, Alexandros, Tius, Marcus A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.01.2003; Amer Chemical Soc
• Subjects: Cannabinoids - chemical synthesis; Cannabinoids - pharmacology; Chemistry; Chemistry, Organic; Combinatorial Chemistry Techniques; Cyclization; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Iodine Radioisotopes - chemistry; Isotope Labeling; Ligands; Models, Molecular; Molecular Probes; Molecular Structure; Organic chemistry; Oxidation-Reduction; Physical Sciences; Preparations and properties; Receptors, Cannabinoid; Receptors, Drug - chemistry; Science & Technology; Stereoisomerism; Structure-Activity Relationship; ALCOHOLS; SYSTEM; ALLYL ETHERS; KETONES; CONVERSION; AFFINITY IRREVERSIBLE PROBE; DEPROTECTION; Radiolabelling; Ligand; Diels Alder addition; Molecular interaction; Oxygen heterocycle; Iodine Organic compounds; Enynic compound; Aminoacid; Cannabinoid receptor; Organic isothiocyanate; Aromatic compound; Chemical synthesis; Triol
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0264978

The main psychoactive constituent of marijuana, (−)-Δ9-tetrahydrocannabinol, produces most of its physiological effects by interacting with the CB1 cannabinoid receptor, a membrane protein belonging to the large superfamily of G-protein coupled receptors. The 3-D structure of the receptor binding site is of value in the design of novel medications for a variety of therapeutic indications. To obtain information on the amino acid residues associated with this binding site, we have designed and synthesized a cannabinergic CB1 ligand prototype carrying an electrophilic isothiocyanato group capable of reacting covalently with amino acid residues bearing thiol or unprotonated amino groups. The ligand also incorporates an iodide atom, which can serve as a high-activity radiolabel. The key step in our synthesis involves a rapid intramolecular Diels−Alder reaction of a transiently formed o-quinone methide, which proceeds stereospecifically with the formation of the tricyclic cannabinoid template. Introduction of the iodo group is the last step in the sequence and is compatible with the use of 125I-radiolabel.