Many non-cardiovascular drugs of common clinical use cause, as an unwanted accessory property, the prolongation of the cardiac repolarisation process, due to the block of the HERG (Human Ether-a-go-go Related Gene) potassium channel, responsible for the repolarising I(Kr) current. This delayed cardiac repolarisation process can be often unmasked by a prolongation of the QT interval of the ECG. In these conditions, premature action potentials can generate morphologically anomalous after-polarisations, and trigger a dangerous kind of polymorphic ventricular tachyarrhythmia, known as torsade de pointes, which can evolve in ventricular fibrillation and death. The risk associated with the torsadogenic cardiotoxicity of drugs, which prolong the QT interval has been the topic of documents produced by many health authorities, giving important issues about the preclinical and clinical evaluation of cardiac safety. Besides, public and private research laboratories developed several experimental in vitro or in vivo strategies, aimed to an early recognition of the influence of a drug (or of a drug-candidate) on the HERG channel and/or on the cardiac repolarisation process. Also the identification of a possible pharmacophore model, common in all or at least in numerous torsadogenic drugs, could represent a first step for the development of useful in silico approaches, allowing a preliminary indication about the potential torsadogenic property of a given molecule. In this work, we described the electrophysiological basis of torsade de pointes and listed several pharmacological classes of torsadogenic drugs. Among them, we focused our attention on antipsychotics, with an accurate overview on the experimental and clinical reports about their torsadogenic properties. Moreover, a common structural feature exhibited by these drugs, despite of their remarkable chemical differences, is evidenced by a computational approach and is indicated as a possible "facilitating" requirement for their torsadogenic properties. Together with other remarks, coming from different computational studies, the individuation of a satisfactory "toxicophore" model could be greatly useful, for the theoretical prediction of torsadogenic properties of a given chemical moiety and for the design of new drugs devoid of such an undesired and potentially lethal side-effect.
Selective inhibitors of CYP24A1 represent an important synthetic target in a search for novel vitamin D compounds of therapeutic value. In the present work, we show the synthesis and biological properties of two novel side chain modified 2-methylene-19-nor-1,25(OH)2D3 analogs, the 22-imidazole-1-yl derivative 2 (VIMI) and the 25-N-cyclopropylamine compound 3 (CPA1), which were efficiently prepared in convergent syntheses utilizing the Lythgoe type Horner–Wittig olefination reaction. When tested in a cell-free assay, both compounds were found to be potent competitive inhibitors of CYP24A1, with the cyclopropylamine analog 3 exhibiting an 80–1 selective inhibition of CYP24A1 over CYP27B1. Addition of 3 to a mouse osteoblast culture sustained the level of 1,25(OH)2D3, further demonstrating its effectiveness in CYP24A1 inhibition. Importantly, the in vitro effects on human promyeloid leukemia (HL-60) cell differentiation by 3 were nearly identical to those of 1,25(OH)2D3 and in vivo the compound showed low calcemic activity. Finally, the results of preliminary theoretical studies provide useful insights to rationalize the ability of analog 3 to selectively inhibit the cytochrome P450 isoform CYP24A1.
1 Endogenous and synthetic cannabinoid molecules have been investigated as possible MDR-1/Pglycoprotein (P-gp) modulators in HK-2-immortalized renal cells, using calcein acetoxymethylester (calcein-AM) as a P-gp substrate.2 Among the endocannabinoid molecules tested, anandamide (AEA), but not 2-arachidonoylglycerol (2-AG) or palmitoyl-ethanolamide (PEA), increased the intracellular fluorescence emitted by calcein, a metabolic derivative of the P-gp substrate calcein-AM, indicative of a reduction in transport capacity. 3 All the three synthetic cannabimimetics tested, that is, R-( þ )-methanandamide (R( þ )-MET), AM 251 and CP55,940 significantly increased calcein accumulation in the cytosol. 4 RT-PCR demonstrated that HK-2 cells do not express CB 1 or CB 2 cannabinoid receptors. 5 R( þ )-MET, AM251 and CP55,940 were also evaluated as modulators of P-gp expression, by Western blot analysis. Only AM251 weakly enhanced the protein levels (by 1.2-fold) after a 4-day-long incubation with the noncytotoxic drug concentration 2 mM. 6 The present data provide the first evidence that the endocannabinoid AEA and different synthetic cannabinoids may inhibit the P-gp activity in vitro via a cannabinoid receptor-independent mechanism.
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