3,5-Dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine (DP7) as a new multidrug resistance reverting agent devoid of effects on vascular smooth muscle contractility

Simona Saponara, Masami Kawase, Anamik Shah, Noboru Motohashi, J. Molnár, Katalin Ugocsai, Giampietro Sgaragli, Fabio Fusi

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

1. The aim of this study was to investigate the effects of 3,5-diacetyl- (DP1-DP5) and 3,5-dibenzoyl-1,4-dihydropyridines (DP6-DP11) on vascular functions in vitro, by comparing their mechanical and electrophysiological actions in rat aorta rings and single rat tail artery myocytes, respectively, and to quantify their multidrug resistance (MDR)-reversing activity in L5178 Y mouse T-lymphoma cells transfected with MDR1 gene. 2. In rat aorta, the 11 compounds tested, but 3,5-dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6- dimethylpyridine (DP7), 3,5-dibenzoyl-4-(3-chlorophenyl)-1,4-dihydro-2,6- dimethylpyridine (DP9), 3,5-dibenzoyl-4-(4-chlorophenyl)-1,4-dihydro-2,6- dimethylpyridine (DP10) and 3,5-dibenzoyl-4-phenyl-1,4-dihydro-2,6- dimethylpyridine (DP11), antagonized 60 mM K + (K60)-induced contraction in a concentration-dependent manner, with IC 50 (M) values ranging between 5.65 × 10 -7 and 2.23 × 10 -5. 3. The 11 dihydropyridines tested, but DP7, inhibited L-type Ca 2+ current recorded in artery myocytes in a concentration- dependent manner, with IC 50 (M) values ranging between 1.12 × 10 -6 and 6.90 × 10 -5. 4. The K +-channel opener cromakalim inhibited the Ca 2+-induced contraction in K30 but not that evoked in K60. On the contrary, DP7 was ineffective in both experimental conditions. 5. When the rings were preincubated with 1 mM Ni 2+ plus 1 μM nifedipine, the response to phenylephrine was significantly reduced by 2,5-di-t-butyl-1,4-benzohydroquinone (BHQ), a well-known endoplasmic reticulum Ca 2+-ATPase inhibitor. DP7 had no effects on this model system. 6. In L5178 MDR cell line, the 11 dihydropyridines tested, but 3,5-diacetyl-4-(2-nitrophenyl)-1,4-dihydro-2,6- dimethylpyridine (DP1), 3,5-diacetyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6- dimethylpyridine (DP2) and 3,5-diacetyl-4-(3-chlorophenyl)-1,4-dihydro-2,6- dimethylpyridine (DP4), exhibited an MDR-reversing activity, with IC 50 values ranging between 3.02 × 10 -7 and 4.27 × 10 -5, DP7 being the most potent. 7. In conclusion, DP7 may represent a lead compound for the development of potent dihydropyridine MDR chemosensitizers devoid of vascular effects.

Original languageEnglish
Pages (from-to)415-422
Number of pages8
JournalBritish Journal of Pharmacology
Volume141
Issue number3
DOIs
Publication statusPublished - Feb 2004

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Multiple Drug Resistance
Vascular Smooth Muscle
Diacetyl
Dihydropyridines
Muscle Cells
Blood Vessels
Aorta
Arteries
Cromakalim
T-Cell Lymphoma
Phenylephrine
Nifedipine
Endoplasmic Reticulum
Adenosine Triphosphatases
3,5-dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine
2,6-lutidine
Tail
Cell Line
Genes

Keywords

  • Dihydropyridines
  • L-type Ca channel inhibitor
  • MDR reverter
  • Mouse T-lymphoma cell
  • Rat aorta ring
  • Rat tail artery smooth muscle
  • Rhodamine 123
  • Whole-cell patch-clamp

ASJC Scopus subject areas

  • Pharmacology

Cite this

3,5-Dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine (DP7) as a new multidrug resistance reverting agent devoid of effects on vascular smooth muscle contractility. / Saponara, Simona; Kawase, Masami; Shah, Anamik; Motohashi, Noboru; Molnár, J.; Ugocsai, Katalin; Sgaragli, Giampietro; Fusi, Fabio.

In: British Journal of Pharmacology, Vol. 141, No. 3, 02.2004, p. 415-422.

Research output: Contribution to journalArticle

Saponara, Simona ; Kawase, Masami ; Shah, Anamik ; Motohashi, Noboru ; Molnár, J. ; Ugocsai, Katalin ; Sgaragli, Giampietro ; Fusi, Fabio. / 3,5-Dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine (DP7) as a new multidrug resistance reverting agent devoid of effects on vascular smooth muscle contractility. In: British Journal of Pharmacology. 2004 ; Vol. 141, No. 3. pp. 415-422.
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T1 - 3,5-Dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine (DP7) as a new multidrug resistance reverting agent devoid of effects on vascular smooth muscle contractility

AU - Saponara, Simona

AU - Kawase, Masami

AU - Shah, Anamik

AU - Motohashi, Noboru

AU - Molnár, J.

AU - Ugocsai, Katalin

AU - Sgaragli, Giampietro

AU - Fusi, Fabio

PY - 2004/2

Y1 - 2004/2

N2 - 1. The aim of this study was to investigate the effects of 3,5-diacetyl- (DP1-DP5) and 3,5-dibenzoyl-1,4-dihydropyridines (DP6-DP11) on vascular functions in vitro, by comparing their mechanical and electrophysiological actions in rat aorta rings and single rat tail artery myocytes, respectively, and to quantify their multidrug resistance (MDR)-reversing activity in L5178 Y mouse T-lymphoma cells transfected with MDR1 gene. 2. In rat aorta, the 11 compounds tested, but 3,5-dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6- dimethylpyridine (DP7), 3,5-dibenzoyl-4-(3-chlorophenyl)-1,4-dihydro-2,6- dimethylpyridine (DP9), 3,5-dibenzoyl-4-(4-chlorophenyl)-1,4-dihydro-2,6- dimethylpyridine (DP10) and 3,5-dibenzoyl-4-phenyl-1,4-dihydro-2,6- dimethylpyridine (DP11), antagonized 60 mM K + (K60)-induced contraction in a concentration-dependent manner, with IC 50 (M) values ranging between 5.65 × 10 -7 and 2.23 × 10 -5. 3. The 11 dihydropyridines tested, but DP7, inhibited L-type Ca 2+ current recorded in artery myocytes in a concentration- dependent manner, with IC 50 (M) values ranging between 1.12 × 10 -6 and 6.90 × 10 -5. 4. The K +-channel opener cromakalim inhibited the Ca 2+-induced contraction in K30 but not that evoked in K60. On the contrary, DP7 was ineffective in both experimental conditions. 5. When the rings were preincubated with 1 mM Ni 2+ plus 1 μM nifedipine, the response to phenylephrine was significantly reduced by 2,5-di-t-butyl-1,4-benzohydroquinone (BHQ), a well-known endoplasmic reticulum Ca 2+-ATPase inhibitor. DP7 had no effects on this model system. 6. In L5178 MDR cell line, the 11 dihydropyridines tested, but 3,5-diacetyl-4-(2-nitrophenyl)-1,4-dihydro-2,6- dimethylpyridine (DP1), 3,5-diacetyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6- dimethylpyridine (DP2) and 3,5-diacetyl-4-(3-chlorophenyl)-1,4-dihydro-2,6- dimethylpyridine (DP4), exhibited an MDR-reversing activity, with IC 50 values ranging between 3.02 × 10 -7 and 4.27 × 10 -5, DP7 being the most potent. 7. In conclusion, DP7 may represent a lead compound for the development of potent dihydropyridine MDR chemosensitizers devoid of vascular effects.

AB - 1. The aim of this study was to investigate the effects of 3,5-diacetyl- (DP1-DP5) and 3,5-dibenzoyl-1,4-dihydropyridines (DP6-DP11) on vascular functions in vitro, by comparing their mechanical and electrophysiological actions in rat aorta rings and single rat tail artery myocytes, respectively, and to quantify their multidrug resistance (MDR)-reversing activity in L5178 Y mouse T-lymphoma cells transfected with MDR1 gene. 2. In rat aorta, the 11 compounds tested, but 3,5-dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6- dimethylpyridine (DP7), 3,5-dibenzoyl-4-(3-chlorophenyl)-1,4-dihydro-2,6- dimethylpyridine (DP9), 3,5-dibenzoyl-4-(4-chlorophenyl)-1,4-dihydro-2,6- dimethylpyridine (DP10) and 3,5-dibenzoyl-4-phenyl-1,4-dihydro-2,6- dimethylpyridine (DP11), antagonized 60 mM K + (K60)-induced contraction in a concentration-dependent manner, with IC 50 (M) values ranging between 5.65 × 10 -7 and 2.23 × 10 -5. 3. The 11 dihydropyridines tested, but DP7, inhibited L-type Ca 2+ current recorded in artery myocytes in a concentration- dependent manner, with IC 50 (M) values ranging between 1.12 × 10 -6 and 6.90 × 10 -5. 4. The K +-channel opener cromakalim inhibited the Ca 2+-induced contraction in K30 but not that evoked in K60. On the contrary, DP7 was ineffective in both experimental conditions. 5. When the rings were preincubated with 1 mM Ni 2+ plus 1 μM nifedipine, the response to phenylephrine was significantly reduced by 2,5-di-t-butyl-1,4-benzohydroquinone (BHQ), a well-known endoplasmic reticulum Ca 2+-ATPase inhibitor. DP7 had no effects on this model system. 6. In L5178 MDR cell line, the 11 dihydropyridines tested, but 3,5-diacetyl-4-(2-nitrophenyl)-1,4-dihydro-2,6- dimethylpyridine (DP1), 3,5-diacetyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6- dimethylpyridine (DP2) and 3,5-diacetyl-4-(3-chlorophenyl)-1,4-dihydro-2,6- dimethylpyridine (DP4), exhibited an MDR-reversing activity, with IC 50 values ranging between 3.02 × 10 -7 and 4.27 × 10 -5, DP7 being the most potent. 7. In conclusion, DP7 may represent a lead compound for the development of potent dihydropyridine MDR chemosensitizers devoid of vascular effects.

KW - Dihydropyridines

KW - L-type Ca channel inhibitor

KW - MDR reverter

KW - Mouse T-lymphoma cell

KW - Rat aorta ring

KW - Rat tail artery smooth muscle

KW - Rhodamine 123

KW - Whole-cell patch-clamp

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