Evaluation of analgesic and anti-inflammatory activity of purine-2,6-dione-based TRPA1 antagonists with PDE4/7 inhibitory activity.

BACKGROUND: To verify the validity of the proposed pain treatment approach, which is based on concomitant blocking of the Transient Receptor Potential Ankyrin 1 (TRPA1) channel and phosphodiesterases (PDEs) 4B/7A activity, we continued our pharmacological studies on 8-alkoxypurine-2,6-diones selected based on previous in vitro screening. METHODS: Derivatives 17, 31, and 36 were pharmacologically evaluated in vivo using the formalin test and oxaliplatin-induced neuropathic pain: the von Frey and the cold plate tests, and in the carrageenan-induced edema model. Compound 36, which turned out to be the most promising, was further evaluated in the collagen-induced arthritis model. The pharmacokinetic parameters of this compound were also estimated. RESULTS: All the tested compounds exhibited significant analgesic and anti-inflammatory activities. Compound 36 was additionally characterized by an antiarthritic effect and showed a favorable pharmacokinetic profile in rats. CONCLUSION: The compounds evaluated in this study represent a new class of derivatives with analgesic and anti-inflammatory activities that involve TRPA1 antagonism and PDE4/7 inhibition.

8-Benzylaminoxanthine scaffold variations for selective ligands acting on adenosine A2A receptors. Design, synthesis and biological evaluation.

A library of 34 novel compounds based on a xanthine scaffold was explored in biological studies for interaction with adenosine receptors (ARs). Structural modifications of the xanthine core were introduced in the 8-position (benzylamino and benzyloxy substitution) as well as at N1, N3, and N7 (small alkyl residues), thereby improving affinity and selectivity for the A2A AR. The compounds were characterized by radioligand binding assays, and our study resulted in the development of the potent A2A AR ligands including 8-((6-chloro-2-fluoro-3-methoxybenzyl)amino)-1-ethyl-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (12d; Ki human A2AAR: 68.5 nM) and 8-((2-chlorobenzyl)amino)-1-ethyl-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (12h; Ki human A2AAR: 71.1 nM). Moreover, dual A1/A2AAR ligands were identified in the group of 1,3-diethyl-7-methylxanthine derivatives. Compound 14b displayed Ki values of 52.2 nM for the A1AR and 167 nM for the A2AAR. Selected A2AAR ligands were further evaluated as inactive for inhibition of monoamine oxidase A, B and isoforms of phosphodiesterase-4B1, -10A, which represent classical targets for xanthine derivatives. Therefore, the developed 8-benzylaminoxanthine scaffold seems to be highly selective for AR activity and relevant for potent and selective A2A ligands. Compound 12d with high selectivity for ARs, especially for the A2AAR subtype, evaluated in animal models of inflammation has shown anti-inflammatory activity. Investigated compounds were found to display high selectivity and may therefore be of high interest for further development as drugs for treating cancer or neurodegenerative diseases.

Synthesis and Determination of Lipophilicity, Anticonvulsant Activity, and Preliminary Safety of 3-Substituted and 3-Unsubstituted N-[(4-Arylpiperazin-1-yl)alkyl]pyrrolidine-2,5-dione Derivatives.

A new series of 1,3-substituted pyrrolidine-2,5-dione derivatives as potential anticonvulsant agents are described. Initial pharmacological screening of these compounds was performed by using acute models of seizures (MES and scPTZ tests) in mice after intraperitoneal administration. Quantitative pharmacological research revealed that the most promising compounds were N-[{4-(3-trifluoromethylphenyl)piperazin-1-yl}propyl]-3-benzhydrylpyrrolidine-2,5-dione monohydrochloride (11) with a ED50 value of 75.9 mg kg-1 (MES test) and N-[{4-(3,4-dichlorophenyl)piperazin-1-yl}ethyl]-3-methylpyrrolidine-2,5-dione monohydrochloride (18) with ED50 =88.2 mg kg-1 (MES test) and ED50 =65.7 kg mg-1 (scPTZ test). These compounds displayed a more beneficial protective index than well-known antiepileptic drugs. A plausible mechanism of action of compounds 11 and 18 [molecule 11 blocked the sodium channel (site 2) and 18 blocked both the sodium (site 2) and L-type calcium channels] and their preliminary safety in vitro were evaluated. Besides, the lipophilicity of all synthesized compounds was determined by using UPLC-MS.