Substituted 5,5'-diphenyl-2-thioxoimidazolidin-4-one as CB1 cannabinoid receptor ligands: synthesis and pharmacological evaluation.
A set of 30 substituted 5,5'-diphenyl-2-thioxoimidazolidin-4-one (thiohydantoins) derivatives was synthesized, and their affinity for the human CB(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 [(35)S]GTPgammaS 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.
Muccioli
Giulio G
GG
Unité de Chimie Pharmaceutique et de Radiopharmacie, Ecole de Pharmacie, Faculté de Médecine, Université catholique de Louvain, Avenue E. Mounier 73, UCL-CMFA 7340, B-1200 Bruxelles, Belgium.
Martin
Diana
D
Scriba
Gerhard K E
GK
Poppitz
Wolfgang
W
Poupaert
Jacques H
JH
Wouters
Johan
J
Lambert
Didier M
DM
D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D011869:Radioligand Assay; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013867:Thiohydantoins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C500161:3-allyl-5,5'-bis(4-bromophenyl)-2-thioxoimidazolidin-4-one; C500160:5,5'-bis(4-iodophenyl)-3-butyl-2-thioxoimidazolidin-4-one; D048289:Imidazolidines; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D013867:Thiohydantoins