Synthesis and cannabinoid-1 receptor binding affinity of conformationally constrained analogs of taranabant

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 16; pp. 4757 - 4761
• Main Authors: Kopka, Ihor E., Lin, Linus S., Jewell, James P., Lanza, Thomas J., Fong, Tung M., Shen, Chun-Pyn, Lao, Zhege J., Ha, Sookhee, Castonguay, Laurie G., Van der Ploeg, Lex, Goulet, Mark T., Hagmann, William K.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.08.2010; Elsevier
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Anti-Obesity Agents - chemical synthesis; Anti-Obesity Agents - chemistry; Anti-Obesity Agents - pharmacology; Biological and medical sciences; Cannabinoid; CB1R; Computer Simulation; Conformationally constrained; Humans; Medical sciences; Miscellaneous; Models, Molecular; Molecular Conformation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Obesity; Pharmacology. Drug treatments; Protein Binding; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Receptor, Cannabinoid, CB1 - chemistry; Receptor, Cannabinoid, CB1 - metabolism; Obesity; Conformationally constrained; Cannabinoid; CB1R; CB1 cannabinoid receptor; Five membered ring; Nitrogen heterocycle; Modeling; Pyrrolidine derivatives; Pyridine derivatives; Structure activity relation; Chlorine Organic compounds; Six membered ring; Piperidine derivatives; Molecular model; Chemical synthesis; Human; Molecular rigidity; Ligand binding; Four membered ring; Ether; Benzene derivatives; Steric hindrance; In vitro; Biological fixation; Azetidine derivatives; Taranabant; Affinity; Carboxamide; Fluorine Organic compounds; Conformation
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.06.127

The design, synthesis, and binding activity of ring constrained analogs of the acyclic cannabinoid-1 receptor (CB1R) inverse agonist taranabant 1 are described. The initial inspiration for these taranabant derivatives was its conformation 1a, determined by 1H NMR, X-ray, and molecular modeling. The constrained analogs were all much less potent than their acyclic parent structure. The design, synthesis, and binding activity of ring constrained analogs of the acyclic cannabinoid-1 receptor (CB1R) inverse agonist taranabant 1 are described. The initial inspiration for these taranabant derivatives was its conformation 1a, determined by 1H NMR, X-ray, and molecular modeling. The constrained analogs were all much less potent than their acyclic parent structure. The results obtained are discussed in the context of a predicted binding of 1 to a homology model of CB1R.