Synthesis and radioligand binding studies of methoxylated 1,2,3,4-tetrahydroisoquinolinium derivatives as ligands of the apamin-sensitive Ca2+-activated K+ channels.
Several methoxylated 1,2,3,4-tetrahydroisoquinoliniums derived from N-methyl-laudanosine and N-methyl-noscapine were synthesized and evaluated for their affinity for apamin-sensitive binding sites. The quaternary ammonium derivatives have a higher affinity with regard to the tertiary amines. 6,7-Dimethoxy analogues possess a higher affinity than the 6,8- and 7,8-dimethoxy isomers. A 3,4-dimethoxybenzyl or a 2-naphthylmethyl moiety in C-1 position are more favorable than a 3,4-dimethoxyphenethyl group. Smaller groups such as propyl or isobutyl are unfavorable. In 6,7-dimethoxy analogues, increasing the size and lipophilicity with a naphthyl group in the C-1 position leads to a slight increase of affinity, while the same group in the 6,7,8-trimethoxy series is less favorable. The 6,7,8-trimethoxy derivative 3f is the first tertiary amine in the series to possess an affinity close to that of N-methyl-laudanosine and N-methyl-noscapine. Moreover, electrophysiological studies show that the most effective compound 4f blocks the apamin-sensitive afterhyperpolarization in rat dopaminergic neurons.
Graulich
Amaury
A
Drug Research Center, Laboratory of Medicinal Chemistry, University of Liège, avenue de l'Hôpital, 1 (B36), B-4000 Liège 1, Belgium. a.graulich@student.ulg.ac.be
Scuvée-Moreau
Jacqueline
J
Alleva
Livia
L
Lamy
Cédric
C
Waroux
Olivier
O
Seutin
Vincent
V
Liégeois
Jean-François
JF
D000818:Animals; D001030:Apamin / Q000378:metabolism*; D001665:Binding Sites; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D008024:Ligands; D015221:Potassium Channels; D000644:Quaternary Ammonium Compounds; D044005:Tetrahydroisoquinolines; D001030:Apamin; D002118:Calcium; D004298:Dopamine