Inhibition of monoamine oxidase by isoquinoline derivatives. Qualitative and 3D-quantitative structure-activity relationships.
A series of isoquinolines, N-methyl-1,2-dihydroisoquinolines, N-methyl-1,2,3,4-tetrahydroisoquinolines, 1,2,3,4-tetrahydroisoquinolines, and N-methylisoquinolinium ions were tested as inhibitors of monoamine oxidases A and B. All compounds were found to act as reversible and time-independent MAO inhibitors, often with a distinct selectivity towards MAO-A. As a class, the N-methylisoquinolinium ions were found to be the most active MAO-A inhibitors, with N-methyl-6-methoxyisoquinolinium ion emerging as a potent (IC50 = 0.81 microM) and competitive MAO-A inhibitor. Comparative molecular field analysis (CoMFA, a 3D-QSAR method) of MAO-A inhibition was performed using the data reported here and in the literature. Using the steric and lipophilic fields of the inhibitors, quantitative models with reasonable predictive power were obtained that point to the importance of steric, lipophilic, and polar interactions in modulating MAO-A inhibitory activity.
Thull
U
U
Institut de Chimie Thérapeutique, Université de Lausanne, Switzerland.
Kneubühler
S
S
Gaillard
P
P
Carrupt
P A
PA
Testa
B
B
Altomare
C
C
Carotti
A
A
Jenner
P
P
McNaught
K S
KS
D001665:Binding Sites; D007546:Isoquinolines / Q000494:pharmacology*; D008958:Models, Molecular; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D011806:Quinolinium Compounds / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines
D007546:Isoquinolines; D008996:Monoamine Oxidase Inhibitors; D011806:Quinolinium Compounds; D044005:Tetrahydroisoquinolines; C051351:N-methylisoquinolinium; C014843:1,2,3,4-tetrahydroisoquinoline