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Structure‐Activity Relationships of Polycyclic Aromatic Amines with Calcium Channel Blocking Activity
Author(s) -
Malan Sarel F.,
Van der Walt J. Jurgens,
Van der Schyf Cornelius J.
Publication year - 2000
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/(sici)1521-4184(200001)333:1<10::aid-ardp10>3.0.co;2-5
Subject(s) - undecane , chemistry , stereochemistry , phenylhydrazine , calcium channel , calcium , steric effects , skeleton (computer programming) , nitro , medicinal chemistry , organic chemistry , alkyl , computer science , programming language
8‐Benzylamino‐8,11‐oxapentacyclo[5.4.0.0 2,6 .0 3,10 .0 5,9 ]undecane ( 1 ) inhibits the calcium current in L‐type calcium channels. A series of nitrobenzylamines ( 2, 3, 4 ), methoxybenzylamines ( 5, 6, 7 ), methylpyridines ( 8, 9, 10 ), and a phenylhydrazine derivative ( 11 ) of 8,11‐oxapentacyclo[5.4.0.0 2,6 .0 3,10 .0 5,9 ]undecane was synthesized. By substituting the 8,11‐oxapentacyclo‐[5.4.0.0 2,6 .0 3,10 .0 5,9 ]undecane skeleton with 3‐hydroxyhexacyclo‐[6.5.0.0. 3,7 .0 4,12 .0 5,10 .0 9,13 ]tridecane ( 12 ), 8,13‐dioxapenta‐cyclo[6.5.0.0 2,6 .0 5,10 .0 3,11 ]tridecane‐9‐one ( 13 ), and pentacyclo‐[5.4.0.0 2,6 .0 3,10 .0 5,9 ]undecane ( 14 ), the effect of the polycyclic skeleton could also be investigated. Increased inhibition of calcium current was observed with aromatic substitution (especially ortho and meta substitution) in the pentacycloundecane series. The calcium channel activities of the methoxy compounds were slightly higher than those of the corresponding nitro compounds while a definite decrease in activity was observed for the phenylhydrazine and aminomethylpyridine derivatives. Increased inhibition of the calcium current was also observed for structures in which the polycyclic ′cages′ were enlarged. Structure‐activity relationships in this series of compounds therefore appear to be dominated by geometric or steric constraints.