Synthesis of (nor)tropeine (di)esters and allosteric modulation of glycine receptor binding.
(Hetero)aromatic mono- and diesters of tropine and nortropine were prepared. Modulation of [3H]strychnine binding to glycine receptors of rat spinal cord was examined with a ternary allosteric model. The esters displaced [3H]strychnine binding with nano- or micromolar potencies and strong negative cooperativity. Coplanarity and distance of the ester moieties of diesters affected the binding affinity being nanomolar for isophthaloyl-bistropane and nortropeines. Nortropisetron had the highest affinity (K(A) approximately 10 nM). Two esters displayed negative cooperativity with glycine in displacement, while three esters of low-affinity and nortropisetron exerted positive cooperativity with glycine.
Department of Molecular Pharmacology, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1525 Budapest, POB 17, Hungary. maksay@chemres.hu
Gábor
G
Maksay
Péter
P
Nemes
Zoltán
Z
Vincze
Timea
T
Bíró
D000495:Allosteric Site; D000818:Animals; D001667:Binding, Competitive; D004952:Esters; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D018009:Receptors, Glycine / Q000378:metabolism*; D013116:Spinal Cord; D013331:Strychnine / Q000737:chemistry; D014326:Tropanes / Q000138:chemical synthesis / Q000494:pharmacology*
D004952:Esters; D018009:Receptors, Glycine; D014326:Tropanes; C005864:tropine; D013331:Strychnine