Synthesis of heteroaromatic tropeines and heterogeneous binding to glycine receptors.
Heteroaromatic carboxylic esters of (nor)tropine were synthesized. Tropine esters displaced [(3)H]strychnine binding to glycine receptors of rat spinal cord with low Hill slopes. Two-site displacement resulted in nanomolar IC(50,1) and micromolar IC(50,2) values, and IC(50,2)/IC(50,1) ratios up to 615 depending on the heteroaromatic rings and N-methyl substitution. Nortropeines displayed high affinity and low heterogeneity. IC(50,1) and IC(50,2) 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-HT(3) receptors.
Maksay
Gábor
G
Department of Molecular Pharmacology, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1525 Budapest, PO Box 17, Hungary. maksay@chemres.hu
Vincze
Zoltán
Z
Nemes
Péter
P
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D004952:Esters; D020128:Inhibitory Concentration 50; D011485:Protein Binding; D051381:Rats; D018009:Receptors, Glycine / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D013116:Spinal Cord / Q000737:chemistry; D013331:Strychnine / Q000493:pharmacokinetics; D014326:Tropanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics
D004952:Esters; D018009:Receptors, Glycine; D044406:Receptors, Serotonin, 5-HT3; D014326:Tropanes; C005864:tropine; D013331:Strychnine