Synthesis of tropeines and allosteric modulation of ionotropic glycine receptors

Gabor Maksay, Péter Nemes, Tímea Biró

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Twenty esters of 3α- and 3β-hydroxy(nor)tropanes and two amides of 3α-aminotropane were prepared with substituted benzoic acids. These (nor)tropeines inhibited [3H]strychnine binding to glycine receptors in synaptosomal membranes of rat spinal cord. A ternary allosteric model was applied to determine the dissociation constants (KA) of the tropeines having strong negative cooperativities with [3H]strychnine binding (α > 10). KA values about 10 nM are well below those of known allosteric agents. Low concentrations (0.1KA) of the (nor)tropeines potentiated the displacing effects of glycine. Positive cooperativity with glycine (β1) decreased with the increase in concentration and binding affinity of tropeines. Displacing potencies were also measured for [3H]granisetron binding to 5-HT3 type serotonin receptors of rat cerebral cortex. Selectivities to glycine receptors versus 5-HT3 receptors varied within 4 orders of magnitude. Nortropeines might serve as a lead to high-affinity selective allosteric modulators of glycine receptors.

Original languageEnglish
Pages (from-to)6384-6391
Number of pages8
JournalJournal of Medicinal Chemistry
Volume47
Issue number25
DOIs
Publication statusPublished - Dec 2 2004

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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