Synthesis, enantiomeric resolution, and structure-activity relationship study of a series of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene MT2 receptor antagonists

Gilberto Spadoni, Annalida Bedini, Giuseppe Diamantini, Giorgio Tarzia, Silvia Rivara, Simone Lorenzi, Alessio Lodola, Marco Mor, Valeria Lucini, Marilou Pannacci, Alessia Caronno, Franco Fraschini

Research output: Contribution to journalArticlepeer-review

Abstract

Racemic N-(8-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohep-ten-10-ylmethyl) acetamide (compound 5) was previously identified as a novel selective MT 2 antagonist fulfilling the requirements of pharmacophore and 3D QSAR models. In this study the enantiomers of 5 were separated by medium-pressure liquid chromatography and behaved as the racemate. Compound 5 was modified at the acylaminomethyl side chain and at position C8. The resulting analogues generally behaved as melatonin receptor antagonists (GTPγS test) with a modest degree of selectivity (up to 10-fold) for the MT2 receptor. Changes at the amide side chain led to a decrease in binding affinity, whereas 8-acetyl and 8-methyl derivatives 12 and 11, respectively, were as potent as the 8-methoxy parent compound 5. Docking experiments with an MT2 receptor model suggested binding modes consistent with the observed SARs and with the lack of selectivity of the enantiomers of 5.

Original languageEnglish
Pages (from-to)1741-1749
Number of pages9
JournalChemMedChem
Volume2
Issue number12
DOIs
Publication statusPublished - Dec 10 2007

Keywords

  • Docking
  • Medicinal chemistry
  • Melatonin
  • MT antagonists
  • Structure-activity relationships

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

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