Synthesis of Tropeines and Allosteric Modulation of Ionotropic Glycine Receptors

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 (K A) of the tropeines having strong negative cooperativities with [3H]strychnine binding (α > 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 (β < 1) 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.