Synthesis and calcium channel antagonist activity of dialkyl hexahydro-1,2′,6′-trimethyl[bipyridine]-3′,5′-dicarboxylates

Reaction of dialkyl 1′,4′-dihydro-2′,6′-dimethylbipyridine]-3′,5′-dicarboxylates 2 with methyl iodide yielded the corresponding 4′-(1-methylpyridinium) iodide salts 3 in quantitative yield. The sodium borohydride reduction of 3 in aqueous ethanol gave the corresponding dialkyl hexahydro-1,2′,6′-trimethylbipyridine]-3′,5′-dicarboxylate analogs 4–5. The calcium channel antagonist activities for 4–5 were determined using the muscarinic receptor-mediated Ca²⁺-dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative activities for the 3′,5′-diethyl series 5 was 3-tetrahydropyridinyl 5b > 4-tetrahydropyridinyl 5c > 2-tetrahydropyridinyl 5a. Increasing the size of the 3′,5′-alkyl substituents enhanced activity. An approximate 1:1 correlation between the IC₅₀ value for the inhibition of ³H]nitrendipine binding and inhibition of the tonic component of the muscarinic-induced contractile response was observed for 4a and 5b. NMR studies suggest that the 4′-2-(1-methyl-1,2,3,6-tetrahydropyridinyl)] ring systems of 4a and 5a are anti-periplanar to the 1,4-dihydropyridine ring system.