Synthesis of heteroaromatic tropeines and heterogeneous binding to glycine receptors

Heteroaromatic carboxylic esters of (nor)tropine were synthesized. Tropine esters displaced [3H]strychnine binding to glycine receptors of rat spinal cord with low Hill slopes. Two-site displacement resulted in nanomolar IC50,1 and micromolar IC50,2 values, and IC50,2/IC50,1 ratios up to 615 depending on the heteroaromatic rings and N-methyl substitution. Nortropeines displayed high affinity and low heterogeneity. IC50,1 and IC50,2 values of tropeines did not correlate suggesting different binding modes/sites. Glycine potentiated only the nanomolar displacement reflecting positive allosteric interactions and potentiation of ionophore function. Affinities of three (nor)tropeines were different for glycine receptors but identical for 5-HT3 receptors.

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