| 15566307 |
Maksay G, Nemes P, Biro T: Synthesis of tropeines and allosteric modulation of ionotropic glycine receptors. J Med Chem. 2004 Dec 2;47(25):6384-91.
Twenty esters of 3 alpha- and 3beta-hydroxy (nor) tropanes and two amides of 3 alpha-aminotropane were prepared with substituted benzoic acids. These (nor) tropeines inhibited [(3) H] strychnine binding to glycine receptors in synaptosomal membranes of rat spinal cord. A ternary allosteric model was applied to determine the dissociation constants (K (A)) of the tropeines having strong negative cooperativities with [(3) H] strychnine binding (alpha > 10). K (A) values about 10 nM are well below those of known allosteric agents. Low concentrations (0.1K (A)) of the (nor) tropeines potentiated the displacing effects of glycine. Positive cooperativity with glycine (beta < 1) decreased with the increase in concentration and binding affinity of tropeines. Displacing potencies were also measured for [(3) H] granisetron binding to 5-HT (3) type serotonin receptors of rat cerebral cortex. Selectivities to glycine receptors versus 5-HT (3) receptors varied within 4 orders of magnitude. Nortropeines might serve as a lead to high-affinity selective allosteric modulators of glycine receptors. |
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