A set of 30 substituted 5,5′-diphenyl-2-thioxoimidazolidin-4-one (thiohydantoins) derivatives was synthesized, and their affinity for the human CB1 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 [35S]-GTPγS 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 1 cannabinoid receptor described to date for the hydantoin and thiohydantoins series when compared in a same bioassay.
Lambert, D. M. (Contributor), Martin, D. (Contributor), Muccioli, G. (Contributor), Poppitz, W. (Contributor), Poupaert, J. H. (Contributor), Scriba, G. K. E. (Contributor) & WOUTERS, J. (Contributor), Cambridge Crystallographic Data Centre, 1 Jan 2006