Substituted 5,5‘-Diphenyl-2-thioxoimidazolidin-4-one as CB₁ Cannabinoid Receptor Ligands:  Synthesis and Pharmacological Evaluation

Abstract

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.

Biased Agonism and Biased Allosteric Modulation at the CB1Cannabinoid Receptor

“…Cannabinoid equilibrium dissociation constants can differ depending on whether antagonist or agonist radioligands are used (Thomas et al, 1998;Govaerts et al, 2004). Nonetheless, pK i values determined in the current study for CP55940, HU-210, WIN55,212-2, D 9 -THC, anandamide, and methanandamide were in general agreement with those reported previously in membrane-based radioligand binding assays that employed [ 3 H]SR141716A (Thomas et al, 1998;Bisogno et al, 2000;Muccioli et al, 2005;D'Antona et al, 2006). There are no published pK i values for 2-AG using [ 3 H]SR141716A.…”

1-Benzhydryl-3-phenylurea and 1-Benzhydryl-3-phenylthiourea Derivatives: New Templates among the CB1 Cannabinoid Receptor Inverse Agonists

“…We previously described the structure-affinity relationships at the CB 1 cannabinoid receptor of alkyl and alkylaryl 3-substituted 5,5′-diphenylimidazolidine-2,4-diones 15 and 5,5′-diphenyl-2-thioxoimidazolidin-4-ones 16 as selective CB 1 cannabinoid receptor inverse agonists. Therefore, four 3,5,5′-triphenylimidazolidine-2,4-diones (26-29) and two 3,5,5′-triphenyl-2-thioxoimidazolidin-4-one derivatives (30, 31) were synthesized (Scheme 2) and assayed for their CB 1 cannabinoid receptor affinity ( Table 1).…”

“…Cells membranes were obtained as previously described. 16 Stock solutions of the compounds were prepared in DMSO and further diluted (100×) with the binding buffer to the desired concentration. Under these conditions B max was 57 pmol/mg protein and Kd was 1.13 ( 0.13 nM for the hCB1 cannabinoid receptor ( Ci/mol, from NEN Life Science, Zaventem, Belgium) as radioligands for the hCB 1 and the hCB2 cannabinoid receptor, respectively, at 30°C in plastic tubes, and 40 µg of membranes per tube was resuspended in 0.5 mL (final volume) of binding buffer (50 mM Tris-HCl, 3 mM MgCl2, 1 mM EDTA, 0.5% bovine serum albumine, pH 7.4).…”

Structure–Property Relationships and Nonlinear Optical Effects in Donor‐Substituted Dicyanopyrazine‐Derived Push–Pull Chromophores with Enlarged and Varied π‐Linkers

“…Whereas compounds 11 and 12 were commercially available, α-diketones 13 (see ref. [13] ) and 14 were synthesized by the methodology of Faust and Weber. [14] Treatment of 4-ethynyl-N,Ndimethylaniline or 1,4-diodobenzene with nBuLi at -78°C followed by transmetallation with CuBr and subsequent quenching of the copper species with oxalyl chloride provided 4,4Ј-diiodobenzil (13) and extended α-diketone 14 in 48 % yield for both compounds.…”