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Cystic fibrosis: a new target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines.

Budriesi R, Ioan P, Leoni A, Pedemonte N, Locatelli A, Micucci M, Chiarini A, Galietta LJ - J. Med. Chem. (2011)

Bottom Line: Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol.For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J.Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Bologna, 40126 Bologna, Italy.

ABSTRACT
The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol. Pharmacol. 2005 , 68 , 1736 ). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J. Med. Chem. 2008 , 51 , 1592 ) to enhance the activity of ΔF508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.

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Evaluation of selected compounds on CFTR, negative inotropic activity (INO), negative chronotropic activity (CHRONO), vasorelaxation of guinea pig aortic strips (AORTA), ileum longitudinal smooth muscle (GPILSM), and tracheal smooth muscle (TRACHEA). Data are normalized for the most effective compound (100%) in each assay.
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fig2: Evaluation of selected compounds on CFTR, negative inotropic activity (INO), negative chronotropic activity (CHRONO), vasorelaxation of guinea pig aortic strips (AORTA), ileum longitudinal smooth muscle (GPILSM), and tracheal smooth muscle (TRACHEA). Data are normalized for the most effective compound (100%) in each assay.

Mentions: Our study had the main objective of identifying 1,4-DHPs with optimal activity as potentiators of the CFTR Cl– channel and negligible effects on voltage-dependent Ca2+ channels (VDCCs). In a previous paper, it was shown that these two activities might be separated by modifying the substituents of 1,4-DHP scaffold.13 Indeed a cell-based functional assay approach was used to identify compounds, such as 48–50, with high potency and efficacy on mutant CFTR and dramatically reduced activity on VDCCs.13 In the present study, we have proved these results by testing these compounds on physiologically relevant functions associated with Ca2+ channel activity in heart, aorta smooth muscle strips, and ileum. Our results in aortic strips (Figure 2) demonstrate that the CFTR-selective 1,4-DHPs previously identified13 indeed have low potency and efficacy, compared to an antihypertensive drug such as nifedipine, on the contractility of smooth muscle of blood vessels. These compounds, namely, 48–50, also have negligible negative chronotropic activity on the guinea pig right atrium. In contrast, these 1,4-DHPs are similar to nifedipine as negative inotropic agents and also as relaxant agents on intestinal smooth muscle (Tables 3 and 4). These results may reflect a different expression of Ca2+ channel subtypes in tissues used for functional assays. It is known that the activities of the cardiac calcium channel blockers are related to their interaction with the α1-subunits of VDCCs. In particular, the negative inotropic effect is due to interaction with the Cav1.2 isoform while the negative chronotropic effect seems to be related to interaction with the Cav1.3 isoform.22 Furthermore, effects of Ca2+ channel blockers such as nifedipine on vascular and nonvascular smooth muscle cells appear to be linked to the interaction with the Cav1.2 isoform.23 Moreover, the discovery that CFTR is expressed not only in epithelial cells but also in the smooth muscle, where it may modulate contractility, complicates the interpretation of results.24 To address this point, we have also tested a classical non-1,4-DHP CFTR potentiator such as genistein. The finding that genistein has, at least in part, a profile similar to that of CFTR-selective 1,4-DHPs (i.e., low activity on aorta and high relaxant effect on ileum) suggests the possibility that CFTR contributes to smooth muscle function in some organs (Figure 2).


Cystic fibrosis: a new target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines.

Budriesi R, Ioan P, Leoni A, Pedemonte N, Locatelli A, Micucci M, Chiarini A, Galietta LJ - J. Med. Chem. (2011)

Evaluation of selected compounds on CFTR, negative inotropic activity (INO), negative chronotropic activity (CHRONO), vasorelaxation of guinea pig aortic strips (AORTA), ileum longitudinal smooth muscle (GPILSM), and tracheal smooth muscle (TRACHEA). Data are normalized for the most effective compound (100%) in each assay.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108470&req=5

fig2: Evaluation of selected compounds on CFTR, negative inotropic activity (INO), negative chronotropic activity (CHRONO), vasorelaxation of guinea pig aortic strips (AORTA), ileum longitudinal smooth muscle (GPILSM), and tracheal smooth muscle (TRACHEA). Data are normalized for the most effective compound (100%) in each assay.
Mentions: Our study had the main objective of identifying 1,4-DHPs with optimal activity as potentiators of the CFTR Cl– channel and negligible effects on voltage-dependent Ca2+ channels (VDCCs). In a previous paper, it was shown that these two activities might be separated by modifying the substituents of 1,4-DHP scaffold.13 Indeed a cell-based functional assay approach was used to identify compounds, such as 48–50, with high potency and efficacy on mutant CFTR and dramatically reduced activity on VDCCs.13 In the present study, we have proved these results by testing these compounds on physiologically relevant functions associated with Ca2+ channel activity in heart, aorta smooth muscle strips, and ileum. Our results in aortic strips (Figure 2) demonstrate that the CFTR-selective 1,4-DHPs previously identified13 indeed have low potency and efficacy, compared to an antihypertensive drug such as nifedipine, on the contractility of smooth muscle of blood vessels. These compounds, namely, 48–50, also have negligible negative chronotropic activity on the guinea pig right atrium. In contrast, these 1,4-DHPs are similar to nifedipine as negative inotropic agents and also as relaxant agents on intestinal smooth muscle (Tables 3 and 4). These results may reflect a different expression of Ca2+ channel subtypes in tissues used for functional assays. It is known that the activities of the cardiac calcium channel blockers are related to their interaction with the α1-subunits of VDCCs. In particular, the negative inotropic effect is due to interaction with the Cav1.2 isoform while the negative chronotropic effect seems to be related to interaction with the Cav1.3 isoform.22 Furthermore, effects of Ca2+ channel blockers such as nifedipine on vascular and nonvascular smooth muscle cells appear to be linked to the interaction with the Cav1.2 isoform.23 Moreover, the discovery that CFTR is expressed not only in epithelial cells but also in the smooth muscle, where it may modulate contractility, complicates the interpretation of results.24 To address this point, we have also tested a classical non-1,4-DHP CFTR potentiator such as genistein. The finding that genistein has, at least in part, a profile similar to that of CFTR-selective 1,4-DHPs (i.e., low activity on aorta and high relaxant effect on ileum) suggests the possibility that CFTR contributes to smooth muscle function in some organs (Figure 2).

Bottom Line: Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol.For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J.Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Bologna, 40126 Bologna, Italy.

ABSTRACT
The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol. Pharmacol. 2005 , 68 , 1736 ). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J. Med. Chem. 2008 , 51 , 1592 ) to enhance the activity of ΔF508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.

Show MeSH
Related in: MedlinePlus