Substituted 5,5'-Diphenyl-2-thioxoimidazolidin-4-one as CB sub(1) Cannabinoid Receptor Ligands: Synthesis and Pharmacological Evaluation

• Published in: Journal of medicinal chemistry 2005-04, Vol.48 (7), p.2509-2517
• Main Authors: Muccioli, G G, Martin, D, Scriba, GKE, Poppitz, W, Poupaert, J H, Wouters, J, Lambert, D M
• Format: Article
• Language: English
• ISSN: 0022-2623
• DOI: 10.1021/jm049263k

A set of 30 substituted 5,5'-diphenyl-2-thioxoimidazolidin-4-one (thiohydantoins) derivatives was synthesized, and their affinity for the human CB sub(1) cannabinoid receptor has been evaluated. These compounds are derived from the previously described cannabinoid ligands 5,5'-diphenylimidazolidine-2,4-dione (hydantoins). The replacement of the oxygen by a sulfur leads to an increase of the affinity while the function-i.e., inverse agonism-determined by [ super(35)S]GTP gamma S experiments remains unaffected. Finally, to evaluate the molecular parameters that could influence the affinity of the thiohydantoins, molecular electrostatic potential as well as lipophilicity calculations were undertaken on representative thiohydantoins and hydantoins derivatives. In conclusion, 5,5'-bis-(4-iodophenyl)-3-butyl-2-thioxoimidazolidin-4-one (31) and 3-allyl-5,5'-bis(4-bromophenyl)-2-thioxoimidazolidin-4-one (32) possess the highest affinity for the CB sub(1) cannabinoid receptor described to date for the hydantoin and thiohydantoins series when compared in a same bioassay.