M.A. Capo

Synthesis and antinociceptive activity of 9-phenyl-oxy or 9-acyl-oxy derivatives of xanthene, thioxanthene and acridine

The synthesis of 9-alkyl-oxy or 9-acyl-oxy derivatives of xanthene, thioxanthene and acridine is reported. A potent antinociceptive activity was confirmed for the 9-phenyl-9-propionyl-oxy derivative bearing an oxygen or sulfur atom in the heteroaromatic structure.Abstract The synthesis of 9-alkyl-oxy or 9-acyl-oxy derivatives of xanthene, thioxanthene and acridine is reported. A potent antinociceptive activity was confirmed for the 9-phenyl-9-propionyl-oxy derivative bearing an oxygen or sulfur atom in the heteroaromatic structure.

Original paperSynthesis and antinociceptive activity of 9-phenyl-oxy or 9-acyl-oxy derivatives of xanthene, thioxanthene and acridineSynthèse et activité antinociceptive de dérivés phényl-9-alkoxy-9 ou acyl-oxy-9 de xanthène, thioxanthène et acridine

The synthesis of 9-alkyl-oxy or 9-acyl-oxy derivatives of xanthene, thioxanthene and acridine is reported. A potent antinociceptive activity was confirmed for the 9-phenyl-9-propionyl-oxy derivative bearing an oxygen or sulfur atom in the heteroaromatic structure.Abstract The synthesis of 9-alkyl-oxy or 9-acyl-oxy derivatives of xanthene, thioxanthene and acridine is reported. A potent antinociceptive activity was confirmed for the 9-phenyl-9-propionyl-oxy derivative bearing an oxygen or sulfur atom in the heteroaromatic structure.

Higher sensitivity to cadmium induced cell death of basal forebrain cholinergic neurons: a cholinesterase dependent mechanism.

Cadmium is an environmental pollutant, which is a cause of concern because it can be greatly concentrated in the organism causing severe damage to a variety of organs including the nervous system which is one of the most affected. Cadmium has been reported to produce learning and memory dysfunctions and Alzheimer like symptoms, though the mechanism is unknown. On the other hand, cholinergic system in central nervous system (CNS) is implicated on learning and memory regulation, and it has been reported that cadmium can affect cholinergic transmission and it can also induce selective toxicity on cholinergic system at peripheral level, producing cholinergic neurons loss, which may explain cadmium effects on learning and memory processes if produced on central level. The present study is aimed at researching the selective neurotoxicity induced by cadmium on cholinergic system in CNS. For this purpose we evaluated, in basal forebrain region, the cadmium toxic effects on neuronal viability and the cholinergic mechanisms related to it on NS56 cholinergic mourine septal cell line. This study proves that cadmium induces a more pronounced, but not selective, cell death on acetylcholinesterase (AChE) on cholinergic neurons. Moreover, MTT and LDH assays showed a dose dependent decrease of cell viability in NS56 cells. The ACh treatment of SN56 cells did not revert cell viability reduction induced by cadmium, but siRNA transfection against AChE partially reduced it. Our present results provide new understanding of the mechanisms contributing to the harmful effects of cadmium on the function and viability of neurons, and the possible relevance of cadmium in the pathogenesis of neurodegenerative diseases.

Neuroprotective or neurotoxic effects of 4-aminopyridine mediated by KChIP1 regulation through adjustment of Kv 4.3 potassium channels expression and GABA-mediated transmission in primary hippocampal cells.

4-Aminopyridine (4-AP) is a potassium channel blocker used for the treatment of neuromuscular disorders. Otherwise, it has been described to produce a large number of adverse effects among them cell death mediated mainly by blockage of K(+) channels. However, a protective effect against cell death has also been described. On the other hand, Kv channel interacting protein 1 (KChIP1) is a neuronal calcium sensor protein that is predominantly expressed at GABAergic synapses and it has been related with modulation of K(+) channels, GABAergic transmission and cell death. According to this KChIP1 could play a key role in the protective or toxic effects induced by 4-AP. We evaluated, in wild type and KChIP1 silenced primary hippocampal neurons, the effect of 4-AP (0.25μM to 2mM) with or without semicarbazide (0.3M) co-treatment after 24h and after 14 days 4-AP alone exposure on cell viability, the effect of 4-AP (0.25μM to 2mM) on KChIP1 and Kv 4.3 potassium channels gene expression and GABAergic transmission after 24h treatment or after 14 days exposure to 4-AP (0.25μM to1μM). 4-AP induced cell death after 24h (from 1mM) and after 14 days treatment. We observed that 4-AP modulates KChIP1 which regulate Kv 4.3 channels expression and GABAergic transmission. Our study suggests that KChIP1 is a key gene that has a protective effect up to certain concentration after short-term treatment with 4-AP against induced cell injury; but this protection is erased after long term exposure, due to KChIP1 down-regulation predisposing cell to 4-AP induced damages. These data might help to explain protective and toxic effects observed after overdose and long term exposure.

New heteroaryl derivatives of fentanyl

Abstract— The preparation of analogues of fentanyl with N‐phenyl replaced with a heterocyclic aromatic ring, and with N‐alkyl/arylalkyl N‐acyl substituents is reported. Only those compounds carrying an N‐phenylethyl substituent were active in the rat tail‐withdrawal test. Fentanyl (1) is the prototype of the 4‐anilido‐piperidine class of opioid analgesics (Casy & Parfitt 1986). Several recent publications (Casy & Huckstep 1988; Bagley et al 1989) on this series have dealt with heterocyclic and aromatic modifications of the fentanyl molecule. Although the antinociceptive potency of most novel derivatives was greater than that of morphine, they had reduced activity when compared with fentanyl itself. To acquire further information on the structure‐reactivity relationships of the series, new heteroaryl derivatives have been prepared and tested for antinociceptive activity.

Liver and kidney damage induced by 4-aminopyridine in a repeated dose (28 days) oral toxicity study in rats: Gene expression profile of hybrid cell death

4-Aminopyridine (4-AP) is an orphan drug indicated for the treatment of neuromuscular disorders. There is a great controversy around the use of this drug because of its narrow safety index and because a large number of adverse effects have been reported. Moreover, it was shown to induce cell death in different cell lines, being reported mainly apoptosis and necrosis as the principal pathways of cell death mediated by blockage of K channels or the Na, K-ATPase, but until now it was not described in vivo cell death induced by 4-aminipyridine. To provide new subchronic toxicity data and specifically, evaluate if 4-AP is able to induce in vivo cell death process and the main pathways related to it, a repeated dose (28 days) oral toxicity study, at therapeutic range of doses, was conducted in rats. The anatomical pathology, the biochemical and hematological parameters were analyzed and a real-time PCR array analysis was developed with an Ingenuity Pathway Analysis (IPA). The leucocytes number, the lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) enzymatic activity were increased at all dose but the erythrocytes number, the hemoglobin concentration, the alkaline phosphatase (FAL) and alanine aminotransferase (ALT) enzymatic activity were increased only at highest dose studied. However, glucose levels decreased at all doses. The biochemical results are indicative of hepatic damage. The anatomy pathology studies showed cell death only on liver and kidney, and the real-time PCR array on liver tissue expressed a gene expression profile of necrotic and apoptotic induced cell death. The present work shows for the first time in vivo cell death on liver and kidney with features of apoptosis and necrosis induced by 4-AP and the gene expression profile shows that the cell death is mediated by necrotic and apoptotic pathways that support this finding.