99254-95-2

Calcium Channel

McN5691 (1 and 10 μM) prevents 60 mM KCl-induced contraction and calcium uptake and causes concentration-dependent relaxation (EC ₅₀ =190 μM) of 30 mM KCl-contracted aortic rings. At or below 10 μM, McN5691 (McN-5691) has no effects on basal tone or calcium uptake (45Ca) in isolated rings of rabbit thoracic aorta. McN5691 causes complete high affinity inhibition (K _d =39.5 nM) of specific diltiazem binding to the benzothiazepine receptor on the voltage-sensitive calcium channel in skeletal muscle microsomal membranes. In contrast to diltiazem, McN5691 inhibits specific dihydropyridine receptor binding, but the effect is biphasic with high (K _d =4.7 nM) and low (K _d =919.8 nM) affinity components. McN5691 inhibits norepinephrine (NE)-induced contraction (10 μM) and calcium uptake (1 and 10 μM) and causes concentration-dependent relaxation (EC ₅₀ =159 μM) of 1 μM NE-contracted rings of rabbit thoracic aorta.

The excretion and metabolism of a 2-ethynylbenzenealkanamine analog, antihypertensive McN5691 (RWJ-26240), in beagle dogs is investigated. A total of 96.8% and 2.8% of the radioactive dose are excreted in feces and urine, respectively, during the 7 days after oral administration of ¹⁴ C-McN5691. Of the radioactive dose, 96.8% and 2.8% is recovered in feces and urine, respectively, in the 7 days after oral administration of ¹⁴ C-McN5691. More than 87% of the dose is excreted in feces during the 48 hours. McN5691 is extensively metabolized in dogs. Unchanged McN5691 is found in less than 0.1% and 19% of the dose in the 0-24 hour urine and 0-48 hour fecal extract, respectively, and 36% of the sample in the 4 hour plasma. In the McN5691 (McN-5691) study, vascular resistances tend to be higher in spontaneously hypertensive rat (SHR) than in Wistar-Kyoto (WKY) but the differences are statistically significant only in the cerebellum and the midbrain.