Synthesis and Radioligand Binding Studies of C-5- and C-8-Substituted 1-(3,4-Dimethoxybenzyl) -2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums as SK Channel Blockers Related to N-Methyl-laudanosine and N-Methyl-noscapine

摘要

The synthesis and the ~(125)I-apamin binding studies of original C-5- and C-8-substituted l-(3,4-dimethoxy-benzyl)-2,2-dimethyl-l,2,3,4-tetrahydroisoqumoliniums and l-(3,4-dimethoxy-ben-zyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridiniums were performed in order to find a reversible and selective SK channel blocker structurally related to N-methyl-laudanosine and N-methyl-noscapine.A bulky alkyl substituent in the C-8 position of the tetrahydroiso-quinoline produces a clear increase in the affinity for the apamin sensitive binding sites.The presence of an electron-withdrawing group in the C-5 and C-8 positions is not a suitable substitution for the affinity of drugs structurally related to N-methyl-laudanosine.Thiophenic analogues and 8-methoxy derivatives possess a poor affinity for the apamin sensitive binding sites.Electrophysiological studies performed with the most effective compound showed a blockade of the apamin sensitive afterhyperpolarization in rat dopaminergic neurons.