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.
The synthesis and the (125)I-apamin binding studies of original C-5- and C-8-substituted 1-(3,4-dimethoxy-benzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums and 1-(3,4-dimethoxy-benzyl)-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 tetrahydroisoquinoline 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.
Graulich
Amaury
A
Laboratory of Medicinal Chemistry, Natural and Synthetic Drugs Research Center, University of Liège, avenue de l'Hôpital, 1 (B36), B-4000 Liège 1, Belgium. A.Graulich@student.ulg.ac.be
Scuvée-Moreau
Jacqueline
J
Seutin
Vincent
V
Liégeois
Jean-François
JF
D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000737:chemistry*; D008297:Male; D009665:Noscapine / Q000031:analogs & derivatives* / Q000737:chemistry*; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D051640:Small-Conductance Calcium-Activated Potassium Channels; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D007546:Isoquinolines; C502478:N-methyl-laudanosine iodide; C502991:N-methylnoscapine; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D051640:Small-Conductance Calcium-Activated Potassium Channels; D044005:Tetrahydroisoquinolines; D001030:Apamin; D009665:Noscapine