title: Synthesis of tropeines and allosteric modulation of ionotropic glycine receptors.
abstract: Twenty esters of 3 alpha- and 3beta-hydroxy(nor)tropanes and two amides of 3 alpha-aminotropane were prepared with substituted benzoic acids. These (nor)tropeines inhibited [(3)H]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 [(3)H]strychnine binding (alpha > 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 (beta < 1) decreased with the increase in concentration and binding affinity of tropeines. Displacing potencies were also measured for [(3)H]granisetron binding to 5-HT(3) type serotonin receptors of rat cerebral cortex. Selectivities to glycine receptors versus 5-HT(3) receptors varied within 4 orders of magnitude. Nortropeines might serve as a lead to high-affinity selective allosteric modulators of glycine receptors.
authors.affiliation: Molecular Pharmacology Group, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1525 Budapest, Hungary. marksay@chemres.hu
authors.forename: Gábor
authors.initials: G
authors.lastname: Maksay
authors.forename: Péter
authors.initials: P
authors.lastname: Nemes
authors.forename: Tímea
authors.initials: T
authors.lastname: Bíró
mesh_terms: D000494:Allosteric Regulation; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001565:Benzoates / Q000737:chemistry; D001667:Binding, Competitive; D005998:Glycine / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D051381:Rats; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013331:Strychnine / Q000378:metabolism; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D001565:Benzoates; D018009:Receptors, Glycine; D044406:Receptors, Serotonin, 5-HT3; D014326:Tropanes; D013331:Strychnine; D005998:Glycine