Synthesis and calcium channel antagonist activity of dialkyl hexahydro-1,2',6'-trimethyl-3',5'-dicarboxylates

Article abstract of DOI:10.1016/0223-5234(87)90289-3

Reaction of dialkyl 1',4'-dihydro-2',6'-dimethyl-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'-trimethyl-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-periplaner to the 1,4-dihydropyridine ring system.