Synthesis and radioligand binding studies of methoxylated 1,2,3,4-tetrahydroisoquinolinium derivatives as ligands of the apamin-sensitive Ca2+-activated K+ channels.

doi:10.1021/JM0607395

Paper

Synthesis and radioligand binding studies of methoxylated 1,2,3,4-tetrahydroisoquinolinium derivatives as ligands of the apamin-sensitive Ca2+-activated K+ channels.

Published Nov 30, 2006 · A. Graulich, J. Scuvée-Moreau, L. Alleva

Journal of medicinal chemistry

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13

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Abstract

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.

In Vitro Study

Study Snapshot

Methoxylated 1,2,3,4-tetrahydroisoquinolinium derivatives show potential as potent inhibitors of apamin-sensitive Ca2+-activated K+ channels in rat dopaminergic neurons.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Synthesis and radioligand binding studies of methoxylated 1,2,3,4-tetrahydroisoquinolinium derivatives as ligands of the apamin-sensitive Ca2+-activated K+ channels.

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References

Citations

Asymmetric synthesis of six tetrahydroisoquinoline natural products through α-amination of an aldehyde

This study presents an enantioselective route for synthesizing six different C-1 substituted tetrahydroisoquinoline natural products using a single aldehyde and proline-catalyzed asymmetric -hydrazination reaction.

General and Efficient Copper-Catalyzed Oxazaborolidine Complex in Transfer Hydrogenation of Isoquinolines under Mild Conditions

Copper-catalyzed transfer hydrogenation of isoquinolines with an oxazaborolidine-BH3 complex under mild conditions effectively reduces a broad range of isoquinolines to their products, with 61-85% yields.

Photocatalytic deaminative benzylation and alkylation of tetrahydroisoquinolines with N-alkylpyrydinium salts

This study developed a ruthenium-catalyzed photoredox coupling method for fast access to 1-benzyl-THIQs and other secondary alkyl and allyl groups in tetrahydroisoquinolines, enabling N-deprotection and N-deprotecti

Biomimetic Total Synthesis of Dysoxylum Alkaloids.

This study successfully synthesized Dysoxylum alkaloids using a biomimetic approach from zanthoxylamide protoalkaloids, providing insights into their biosynthetic origin and establishing an enantioselectivity-toxicity relationship.

Synthesis of Tetrahydroisoquinoline Alkaloids and Related Compounds through the Alkylation of Anodically Prepared α-Amino Nitriles.

This study demonstrates a facile and efficient method for synthesizing tetrahydroisoquinoline alkaloids and related compounds using anodically prepared -amino nitriles.