DHP-218

Phenyldihydropyridinephosphonates I [RR = (CH₂)₃, CH₂CMe₂CH₂; R = CO₂Me, allyl; R¹ = 2-NO₂, 2-CF₃, 2-OCHF₂, 3-NO₂; R² = Me, CH₂CHMe₂, CH₂CH₂OCH₂Ph, CH₂CH₂OMe, CH₂CH₂NMeCH₂Ph, allyl; R³ = Me, Et, Pr, allyl, CH₂Ph, CH₂CH₂OMe, NMe₂; R⁴ = Me] were prepared by the cyclocondensation reaction of R³NHCMe:CHCO₂R² with R¹C₆H₄CH:CAcP(O)(OR)₂ (II).I [R = allyl, RR = (CH₂)₃; R¹ = 2-NO₂, 3-NO₂, 2-CF₃; R² = Me; R³ = H; R⁴ = CH(OMe)₂] were prepared similarly by the reaction of II with (MeO)₂CHC(NH₂):CHCO₂Me.I [R⁴ = CH(OMe)₂] was deprotected to give I (same R-R³; R⁴ = CHO).The latter were converted to I (R⁴ = CH₂OH, CH:NOH, cyano).I were all tested for antihypertensive activity in normotensive and spontaneously hypertensive rats.I [RR = (CH₂)₃, R¹ = 2-NO₂, R² = Me, R³ = R⁴ = Me] shows higher antihypertensive activity than nifedipine, but lower than DHP-218.

The effects of methyl 2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2- yl)-1,4- dihydropyridine 3-carboxylate (DHP-218), a new dihydropyridine calcium antagonist, on vascular smooth muscles, cardiac muscles and [3H]-nitrendipine binding to the cardiac muscle and brain membranes were investigated in vitro. Vascular smooth muscles: Calcium-induced contraction of the rat aorta in high K+ solution was inhibited by DHP-218 with the pA2 value of 9.11. The IC50 value for the inhibitory effects of this compound in high K+-induced and phenylephrine-induced contraction was 6.3 nmol/l and 66 nmol/l, respectively. Vasodilatory effects of this drug on various blood vessels of rabbits contracted by high K+ appeared to a similar extent. The onset of the vasodilatory effect was very slow and the recovery rate of vasodilatory response after washout with the bathing solution containing high K+ or phenylephrine was also very slow. Cardiac muscles: Negative chronotropic and inotropic actions were observed at concentrations more than 30 and 100 nmol/l, respectively. Duration of the plateau phase of normal action potential was shortened and the amplitude and duration of slow action potential were reduced at concentrations more than 1 mumol/l. Very high vasculoselectivity was observed. Displacement of [3H]-nitrendipine binding: The pattern of displacement of [3H]-nitrendipine binding by DHP-218 was very similar to that of other 1,4-dihydropyridines but this compound was about 70 times less potent than nifedipine in [3H]-nitrendipine displacement capacity. These results indicate that DHP-218 has specific vasodilatory action due to calcium antagonism, but association and dissociation rates with tissue and receptors were different from those of nifedipine.