DHP-218

The effect of DHP-218, a dihydropyridine phosphonate Ca2+ channel blocker, on atrioventricular (AV) nodal conductivity was compared with its vascular effect in dogs. In isolated, blood-perfused AV node preparations, a long-lasting increase in AV conduction time which culminated in second- or third-degree AV block at large doses occurred when DHP-218 was injected into the AV node artery, but not when injected into the artery that supplies the His-Purkinje-ventricular system. However, with DHP-218, a far longer-lasting increase in blood flow through both arteries occurred, and at smaller doses it occurred with little effect on AV conduction. In anesthetized, open-chest dogs of which heart rate was controlled at 150 beats/min, intravenous DHP-218 produced an initially rather quick and later very slowly developing and long-lasting fall in blood pressure. AV conduction time was prolonged only after the largest dose. The functional refractory period of the AV conduction system was rather shortened in all doses examined except for the largest dose. A marked increase in AV conduction time which culminated in third-degree AV block was seen in one of six dogs, only under conditions in which the heart was deprived of central neural control. These results indicate appreciable selectivity of DHP-218 for vasculature versus the AV node.

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.