ABSTRACT
The synthesis and the pharmacological activity of a series of 1-aroyl derivatives of kynurenic acid methyl ester (4-oxo-quinolin-2-carboxy methyl (KYNA) esters), structurally related to NSAID indomethacin are described. The derivatives were screened in vivo for anti-inflammatory and analgesic activities. Most of the compounds exhibited good anti-inflammatory and analgesic activities. An automatic docking of the synthesized compounds was performed using X-ray structures of COX-1 and COX-2. Docking results are in good accordance with the experimental biological data.
Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Kynurenic Acid/analogs & derivatives , Kynurenic Acid/chemical synthesis , Kynurenic Acid/pharmacology , Analgesics/chemistry , Analgesics/metabolism , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/metabolism , Carrageenan/chemistry , Carrageenan/metabolism , Cyclooxygenase 1/pharmacology , Cyclooxygenase 2/chemistry , Cyclooxygenase 2/metabolism , Cyclooxygenase 2/pharmacology , Drug Evaluation, Preclinical , Indomethacin/pharmacology , Kynurenic Acid/chemistry , Models, Molecular , Rats , Structure-Activity RelationshipABSTRACT
Loperamide is a piperidine analogue, acting as agonist on peripheral opioid receptors, exhibiting affinity and selectivity for the cloned mu human opioid receptor compared with the delta human opioid receptor. Automatic docking studies of loperamide, using AutoDock, on human mu- and delta-opioid receptors is described. Whilst no meaningful difference was detected concerning the docking of the arylpiperidine moiety, mu/delta selectivity could be explained as a different accommodation of the two phenyl groups in two lipophylic pockets of receptors.
Subject(s)
Loperamide/metabolism , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/metabolism , Animals , Binding Sites , Computer Simulation , Humans , Models, Molecular , Rats , Receptors, Opioid, delta/chemistry , Receptors, Opioid, mu/chemistryABSTRACT
Loperamide is a well-known peripherally acting opiate used for the treatment of diarrhoea. To gain more knowledge on the structure-activity relationships of antidiarrhoeal drugs and to develop new active molecules, a series of aryl-cyano-piperidinoalkyl-thiazolidinones related to Loperamide was synthesized and screened for antidiarrhoeal activity in mice by castor oil test. To characterize the potency and toxicity of the synthesized compounds ED50 and LD50 values were also determined. The thiazolidinones 2-6 displayed antidiarrhoeal activity at doses ranging between 15 and 82 mg/kg. Although the results show that the synthesized compounds are 15- to 80-fold less active respect to the reference compound, Loperamide, they are much less toxic (> or = 1000 mg/kg and 108.9 mg/kg, respectively). Besides, to evaluate the involvement of opioid receptors in antidiarrhoeal activity, Naloxone was administered prior to test the 2-phenyl-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-one (2), the more active compound of this series. The results obtained by this study, suggest that the antidiarrhoeal activity of this series of thiazolidinone derivatives could involve the opioid receptors.
Subject(s)
Antidiarrheals/chemical synthesis , Antidiarrheals/pharmacology , Diarrhea/drug therapy , Loperamide/analogs & derivatives , Thiazolidinediones/chemical synthesis , Animals , Antidiarrheals/chemistry , Antidiarrheals/therapeutic use , Castor Oil/toxicity , Diarrhea/chemically induced , Loperamide/therapeutic use , Loperamide/toxicity , Mice , Models, Molecular , Naloxone/pharmacology , Structure-Activity Relationship , Thiazolidinediones/chemistryABSTRACT
Novel antitumoral agents with quinonic structure were synthesized and evaluated for their in vitro cytotoxic activities. This study examines the cytotoxic activities of several aryl benzo[g]isoquinoline-5,10-dione derivatives and a number of aminoacyl dihydrothieno[2,3-b]naphtho-4,9-dione (DTNQ) derivatives containing amino acids in position 3 of the ring system. Compound 6 showed remarkable cytotoxic activity at submicromolar concentration not only against several human leukaemia and solid tumour cell lines, but also toward sensitive and resistant human cell lines.
