McN5691 (RWJ26240) is a voltage-dependent calcium channel blocker with antihypertensive activity that can be used in the study of diseases caused by vascular smooth muscle abnormalities.

McN5691 has a complete high-affinity inhibition (Kd=39.5 nM) of specific diltiazem binding to benzothiazepine receptors on voltage-sensitive calcium channels in skeletal muscle microsomal membranes. In contrast to diltiazem, McN5691 inhibited specific dihydropyridine receptor binding, but this effect was biphasic, with both high-affinity (Kd=4.7 nM) and low-affinity (Kd=919.8 nM) components.McN5691 inhibited norepinephrine (NE)-induced constriction (10 μM) and calcium uptake (1 and 10 μM), and caused 1 μM NE contraction of rabbit thoracic aortic rings to produce concentration-dependent relaxation (EC50=159 μM) [1]. McN5691 (1 and 10 μM) prevented 60 mM KCl-induced contraction and calcium uptake and produced concentration-dependent relaxation (EC50=190 μM) in aortic rings contracted with 30 mM KCl. At concentrations of 10 μM or less, McN5691 (McN-5691) had no effect on basal tension or calcium uptake (45Ca) in isolated rings of rabbit thoracic aorta.

McN5691 is extensively metabolized in dogs. In 0-24 hour urine and 0-48 hour fecal extracts, the levels of unchanged McN5691 were less than 0.1% and 19% of the dose, respectively, while in 4-hour plasma, the level of unchanged McN5691 was 36% of the sample [2]. In the McN5691 (McN-5691) study, vascular resistance tended to be higher in spontaneously hypertensive rats (SHR) than in Wistar-Kyoto (WKY), but the difference was only statistically significant in the cerebellum and midbrain [3]. Researchers investigated the excretion and metabolism of the 2-ethynylphenylalkylamine analog, the antihypertensive drug McN5691 (RWJ-26240), in beagles. Within 7 days of oral administration of 14C-McN5691, 96.8% and 2.8% of the radioactive dose was excreted in the feces and urine, respectively. After 7 days of oral administration of 14C-McN5691, 96.8% and 2.8% of the dose was recovered in the feces and urine, respectively. More than 87% of the dose was excreted in the feces within 48 hours.[1]