After the pioneer studies of Fleckenstein and co-workers L-Type calcium channels (LTCC) blockers have attract large interest due to their effectiveness in treating several cardiovascular diseases (1). The 1,4-DHPs are known to be selective for smooth muscle than heart muscle. Nifedipine, the prototype of 1,4-DHP has been largely modified in several position in order to increase its selectivity towards the vascular smooth muscle. In the 1990s different Nifedipine derivatives have been shown to block different types of calcium channels. For these results, new therapeutic indications have been disclosed for the 1,4-DHP scaffold. Among the four classes of LTCC only CaV1.2 and CaV1.3 are pharmacologically targets, since no clinical applications have been proposed for CaV1.1 and CaV1.4 channels. Both CaV1.2 and CaV1.3 channels are expressed in the cardiovascular system where they exert different functions. CaV1.2 channels control vascular tone and cardiac inotropy whereas CaV1.3 channels have a key role in the atrioventricular conduction system. In the central nervous system (CNS), CaV1.2 channels are involved in depressant-like and Parkinson diseases. Nifedipine cause a variety of brain effect such as amelioration of age-related working memory deficits, anxiolytic and antidepressant-like actions and anticonvulsivant effects. In addition, it has to be considered the problem related to its therapeutic use for CNS diseases as the selectivity between central and peripheral LTCC. Recently we describe the design, the synteshis and the structure activity relationship (SAR) of a small library of 1,4-DHPs with a imidazo[2,1-b]thiazole system variously replaced in C4. The chemical changes made, along with the profile of activity shown on isolated cardiac tissues made it possible to correlate the selectivity and potency in cardiac parameters with singular substituents in etherocyclic sistem. Using a ligand based approach and taking into account the inotropic or chronotropic selectivity of compounds, we design new compounds with the aime to improve seletivity. Based on these consideration, the development of selective modulators would make CaV1.3 channels suitable target to treat Parkinson disease, depression and drug abuse. Since most of these SARs are common to all 1,4-DHPs we can conclude that the 1,4-DHP binding site of CaV1.2 and CaV1.3 channels are very similar and the identification of potent and selective compounds will be a hard task. (1) Ioan, P.; Carosati, E.; Micucci, M.; Cruciani, G.; Broccatelli, F.; Zhorov, B. S.; Chiarini, A.; Budriesi, R. Curr. Med. Chem. 2011, 18, 4901-4922. (2) Budriesi, R.; Ioan, P.; Locatelli, A.; Cosconati, S.; Leoni, A.; Ugenti, M. P.; Andreani, A.; Di Toro, R.; Bedini, A.; Spampinato, S.; Marinelli, L.; Novellino, E.; Chiarini, A. J. Med. Chem. 2008, 51, 1592-1600.

1,4-DHP scaffold: calcium channel ligand based approach from cardiovascular to neuroprotective activity.

BUDRIESI, ROBERTA
2012

Abstract

After the pioneer studies of Fleckenstein and co-workers L-Type calcium channels (LTCC) blockers have attract large interest due to their effectiveness in treating several cardiovascular diseases (1). The 1,4-DHPs are known to be selective for smooth muscle than heart muscle. Nifedipine, the prototype of 1,4-DHP has been largely modified in several position in order to increase its selectivity towards the vascular smooth muscle. In the 1990s different Nifedipine derivatives have been shown to block different types of calcium channels. For these results, new therapeutic indications have been disclosed for the 1,4-DHP scaffold. Among the four classes of LTCC only CaV1.2 and CaV1.3 are pharmacologically targets, since no clinical applications have been proposed for CaV1.1 and CaV1.4 channels. Both CaV1.2 and CaV1.3 channels are expressed in the cardiovascular system where they exert different functions. CaV1.2 channels control vascular tone and cardiac inotropy whereas CaV1.3 channels have a key role in the atrioventricular conduction system. In the central nervous system (CNS), CaV1.2 channels are involved in depressant-like and Parkinson diseases. Nifedipine cause a variety of brain effect such as amelioration of age-related working memory deficits, anxiolytic and antidepressant-like actions and anticonvulsivant effects. In addition, it has to be considered the problem related to its therapeutic use for CNS diseases as the selectivity between central and peripheral LTCC. Recently we describe the design, the synteshis and the structure activity relationship (SAR) of a small library of 1,4-DHPs with a imidazo[2,1-b]thiazole system variously replaced in C4. The chemical changes made, along with the profile of activity shown on isolated cardiac tissues made it possible to correlate the selectivity and potency in cardiac parameters with singular substituents in etherocyclic sistem. Using a ligand based approach and taking into account the inotropic or chronotropic selectivity of compounds, we design new compounds with the aime to improve seletivity. Based on these consideration, the development of selective modulators would make CaV1.3 channels suitable target to treat Parkinson disease, depression and drug abuse. Since most of these SARs are common to all 1,4-DHPs we can conclude that the 1,4-DHP binding site of CaV1.2 and CaV1.3 channels are very similar and the identification of potent and selective compounds will be a hard task. (1) Ioan, P.; Carosati, E.; Micucci, M.; Cruciani, G.; Broccatelli, F.; Zhorov, B. S.; Chiarini, A.; Budriesi, R. Curr. Med. Chem. 2011, 18, 4901-4922. (2) Budriesi, R.; Ioan, P.; Locatelli, A.; Cosconati, S.; Leoni, A.; Ugenti, M. P.; Andreani, A.; Di Toro, R.; Bedini, A.; Spampinato, S.; Marinelli, L.; Novellino, E.; Chiarini, A. J. Med. Chem. 2008, 51, 1592-1600.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/144348
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