Palladium-benzodiazepine derivatives as promising metallodrugs for the development of antiepileptic therapies.

Abstract

We synthesized two organometallic diazepam-palladium(II) derivatives by C-H activation of diazepam (DZP) with palladium salts, i.e., PdCl2 and Pd(OAc)2 (OAc=acetate). Both compounds obtained are air stable and were isolated in good yields. The anticonvulsant potential of the complexes, labeled [(DZP)PdCl]2 and [(DZP)PdOAc]2, was evaluated through two animal models: pentylenetetrazole (PTZ)- and picrotoxin (PTX)-induced convulsions. The organometallic DZP-palladium(II) acetate complex, [(DZP)PdOAc]2, significantly increased (p<0.01 or p<0.001) latencies and protected the animals against convulsions induced by PTZ and PTX, while the analogous chloro derivative, [(DZP)PdCl]2, was effective (p<0.01) only in the PTZ model. These effects appear to be mediated through the GABAergic system. The possible mechanism of action of the DZP-palladium(II) complexes was also confirmed with the use of flumazenil (FLU), a GABAA-benzodiazepine receptor complex site antagonist. Herein, we present the first report of the anticonvulsant properties of organometallic DZP-palladium(II) complexes as well as evidence that these compounds may play an important role in the study of new drugs to treat patients with epilepsy.

• Authors: Walleska Bismaida Zacarias Galvão Barros, Allysson Haide Queiroz da Silva, Ana Soraya Lima Barbosa, Ábner Magalhães Nunes, José Rui Machado Reys, Heitor Gomes de Araújo-Filho, Jullyana de Souza Siqueira Quintans, Lucindo José Quintans-Júnior, Michel Pfeffer, Valéria Rodrigues Dos Santos Malta, Mario Roberto Meneghetti
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 155 Pg. 129-35 (Feb 2016) ISSN: 1873-3344 [Electronic] United States
• PMID: 26687024 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Anticonvulsants
• Benzodiazepines
• Palladium

Topics

• Animals
• Anticonvulsants (chemistry, pharmacology)
• Benzodiazepines (chemistry)
• Male
• Mice
• Palladium (chemistry)