title: Hyperekplexia mutation R271L of alpha1 glycine receptors potentiates allosteric interactions of nortropeines, propofol and glycine with [3H]strychnine binding.
abstract: Human alpha1 and hyperekplexia mutant alpha1(R271L) glycine receptors (GlyRs) were transiently expressed in human embryonic kidney 293 cells for [3H]strychnine binding. Binding parameters were determined using a ternary allosteric model. The hyperekplexia mutation increased the positive cooperativity of 0.3 mM propofol and glycine binding by about six times: the cooperativity factor beta was 0.26 for alpha1 GlyRs and 0.04 for alpha1(R271L) GlyRs. Thus, propofol restored the potency of glycine impaired by the mutation. Five nortropeines, i.e. substituted benzoates of nortropine and a new compound, nortropisetron were prepared and also examined on [3H]strychnine binding. They showed nanomolar displacing potencies amplified by the hyperekplexia mutation. The affinity of nor-O-zatosetron (2.6 nM) is one of the highest reported for GlyRs. This binding test offers an in vitro method to evaluate agents against neurological disorders associated with inherited mutations of GlyRs.
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1525 Budapest, POB 17, Hungary. maksay@chemres.hu
authors.forename: Gábor
authors.initials: G
authors.lastname: Maksay
authors.forename: Tímea
authors.initials: T
authors.lastname: Bíró
authors.forename: Bodo
authors.initials: B
authors.lastname: Laube
authors.forename: Péter
authors.initials: P
authors.lastname: Nemes
mesh_terms: D000494:Allosteric Regulation; D002460:Cell Line; D005998:Glycine / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D015742:Propofol / Q000494:pharmacology*; D011487:Protein Conformation; D011869:Radioligand Assay; D018009:Receptors, Glycine / Q000737:chemistry / Q000235:genetics*; D013331:Strychnine / Q000378:metabolism*; D014316:Tritium
chemical_list: D018009:Receptors, Glycine; D014316:Tritium; D013331:Strychnine; D005998:Glycine; D015742:Propofol