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

Abstract

New 1-benzhydryl-3-phenylurea derivatives and their 1-benzhydryl-3-phenylthiourea isosteres were synthesized and evaluated for their human CB 1 and CB 2 cannabinoid receptor affinity. These compounds proved to be selective CB 1 cannabinoid receptor ligands, acting as inverse agonists in a [ 35 S]-GTPγS assay. The affinity of 3,5,5′-triphenylimidazolidine-2,4-dione and 3,5,5′-triphenyl-2-thioxoimidazolidin-4-one derivatives, possessing the 1-benzhydryl-3-phenylurea and 1-benzhydryl-3-phenylthiourea moiety, respectively, was also evaluated. In conclusion, the 1-benzhydryl-3-phenylurea scaffold seems to be a new interesting template of CB 1 cannabinoid receptor inverse agonists. IntroductionThe synthesis of the first potent CB 1 cannabinoid receptor antagonist/inverse agonist SR141716A 1 (rimonabant) and the breeding of knock-out CB 1 mice 2,3 confirmed the high therapeutic potential for modulating CB 1 cannabinoid receptor activity. Several CB 1 cannabinoid receptor inverse agonists were shown to reduce food intake, 4,5 ethanol consumption, 6 and nicotine reward 7,8 in animals. Other studies suggested a beneficial effect on septic shock in rats 9 and in gastrointestinal disorders. 10 Subsequent phase II or III clinical trials confirmed the usefulness of such compounds in treating obesity 11,12 and nicotine 11 addictions. Among the cannabinoid receptor antagonists/inverse agonists available, most are constructed around a central heterocyclic ring (pyrazole, triazole, indole, imidazolidinedione, or thioxoimidazolidinone) bearing further substituted aromatic rings. 13 In this paper, we report the CB 1 cannabinoid receptor inverse agonist properties of new compounds that are not built around such a central ring. The 1-benzhydryl-3-phenylurea derivatives described herein exhibited interesting affinities and potencies for the CB 1 cannabinoid receptor. The 1-benzhydryl-3-phenylthiourea isosteres also showed affinity and inverse agonist properties at the CB 1 cannabinoid receptor. The compounds were then compared with the corresponding 3-phenyl-5,5′-diphenylimidazolidine-2,4-dione and 3-phenyl-5,5′-diphenyl-2-thioxoimidazolidin-4-one derivatives.

One-Pot Multicomponent Synthesis of Thiourea Derivatives in Cyclotriphosphazenes Moieties

“…13 C NMR spectra of compound a-f showed good agreement with the corresponded structures with the presence of C=S peak at 181.2-180.9 ppm [28][29][30].…”

Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold

“…The Biltz synthesis was employed by Muccioli et al for the preparation of 3-substituted phenytoin derivatives. 144 The compounds were synthesized in DMSO in the presence of aqueous KOH, under microwave irradiation (nine pulses at 750 W in a domestic microwave equipment). As a variant of the Biltz reaction, N-hydroxy and N-alkoxyureas were reacted with arylglyoxal hydrates to access 3-hydroxy or 3-alkoxy-5arylhydantoins.…”

“…The Biltz synthesis was employed by Muccioli et al for the preparation of 3-substituted phenytoin derivatives . The compounds were synthesized in DMSO in the presence of aqueous KOH, under microwave irradiation (nine pulses at 750 W in a domestic microwave equipment).…”

Synthesis and Evaluation of Iodinated Phenytoin for Antimicrobial Activity

“…Widespread antibiotic usage exerts a selective pressure that acts as a driving force in the development of antibiotic resistance. As resistance develops to "first-line" antibiotics, therapy with new, broad spectrum, more expensive antibiotics increases, but it might be followed by development of resistance to the new class of drugs 13 .…”