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Scientific article
English

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

Published inJournal of medicinal chemistry, vol. 41, no. 20, p. 3812-3820
Publication date1998
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
  • Animals
  • Brain/drug effects/enzymology/ultrastructure
  • Crystallography, X-Ray
  • Linear Models
  • Mitochondria/drug effects/enzymology
  • Models, Molecular
  • Molecular Conformation
  • Monoamine Oxidase Inhibitors/chemical synthesis/chemistry/pharmacology
  • Pyridazines/chemical synthesis/chemistry/pharmacology
  • Pyrimidines/chemical synthesis/chemistry/pharmacology
  • Rats
  • Structure-Activity Relationship
Affiliation Not a UNIGE publication
Citation (ISO format)
ALTOMARE, Cosimo et al. Inhibition of monoamine oxidase-B by condensed pyridazines and pyrimidines: Effects of lipophilicity and structure-activity relationships. In: Journal of medicinal chemistry, 1998, vol. 41, n° 20, p. 3812–3820. doi: 10.1021/jm981005y
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ISSN of the journal0022-2623
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