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.

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 IC₅₀ (M) values ranging between 5.65 × 10^-7 and 2.23 × 10^-5. 3: The 11 dihydropyridines tested, but DP7, inhibited L-type Ca²⁺ current recorded in artery myocytes in a concentration-dependent manner, with IC₅₀ (M) values ranging between 1.12 × 10^-6 and 6.90 × 10^-5. 4: The K⁺-channel opener cromakalim inhibited the Ca²⁺-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 Ni²⁺ 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 Ca²⁺-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 IC₅₀ 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.British Journal of Pharmacology (2004) 141, 415-422. doi:10.1038/sj.bjp.0705635 [ABSTRACT FROM AUTHOR]