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Title

Inhibition of monoamine oxidase-B by condensed pyridazines and pyrimidines: Effects of lipophilicity and structure-activity relationships

Authors
Altomare, Cosimo
Cellamare, S.
Summo, L.
Catto, M.
Carotti, Angelo
Thull, Ulrike
Testa, Bernard
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Published in Journal of Medicinal Chemistry. 1998, vol. 41, no. 20, p. 3812-3820
Abstract A number of condensed pyridazines and pyrimidines were synthesized and tested for their monoamine oxidase-A (MAO-A) and MAO-B inhibitory activity. Their lipophilicity was examined by measuring partition coefficients and RP-HPLC capacity factors, revealing some peculiar electronic and conformational effects. Further insights were obtained by X-ray crystallography and a thermodynamic study of RP-HPLC retention. Structure-activity relations highlighted the main factors determining both selectivity and inhibitory potency. Thus, while most of the condensed pyridazines were reversible inhibitors of MAO-B with little or no MAO-A effects, the pyrimidine derivatives proved to be reversible and selective MAO-A inhibitors. Substituents on the diazine nucleus modulated enzyme inhibition. A QSAR analysis of X-substituted 3-X-phenyl-5H-indeno[1,2-c]pyridazin-5-ones showed lipophilicity to increase MAO-B and not MAO-A inhibitory activity
Keywords AnimalsBrain/drug effects/enzymology/ultrastructureCrystallography, X-RayLinear ModelsMitochondria/drug effects/enzymologyModels, MolecularMolecular ConformationMonoamine Oxidase Inhibitors/chemical synthesis/chemistry/pharmacologyPyridazines/chemical synthesis/chemistry/pharmacologyPyrimidines/chemical synthesis/chemistry/pharmacologyRatsStructure-Activity Relationship
Stable URL http://archive-ouverte.unige.ch/unige:10532
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Other version: http://pubs.acs.org/doi/pdf/10.1021/jm981005y
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PMID: 9748356
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