Synthesis of Tropeines and Allosteric Modulation of Ionotropic Glycine Receptors

Twenty esters of 3α- and 3β-hydroxy(nor)tropanes and two amides of 3α-aminotropane were prepared with substituted benzoic acids. These (nor)tropeines inhibited [3H]strychnine binding to glycine receptors in synaptosomal membranes of rat spinal cord. A ternary allosteric model was applied to determin...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2004-12, Vol.47 (25), p.6384-6391
Main Authors: Maksay, Gábor, Nemes, Péter, Bíró, Tímea
Format: Article
Language:English
Subjects:
Allosteric Regulation
Amides - chemical synthesis
Amides - chemistry
Amides - pharmacology
Animals
Benzoates - chemistry
Binding, Competitive
Biological and medical sciences
Glutamatergic system (aspartate and other excitatory aminoacids)
Glycine - metabolism
In Vitro Techniques
Male
Medical sciences
Models, Molecular
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Rats
Rats, Wistar
Receptors, Glycine - metabolism
Receptors, Serotonin, 5-HT3 - metabolism
Spinal Cord - drug effects
Spinal Cord - metabolism
Structure-Activity Relationship
Strychnine - metabolism
Tropanes - chemical synthesis
Tropanes - chemistry
Tropanes - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Twenty esters of 3α- and 3β-hydroxy(nor)tropanes and two amides of 3α-aminotropane were prepared with substituted benzoic acids. These (nor)tropeines inhibited [3H]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 [3H]strychnine binding (α > 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 (β < 1) decreased with the increase in concentration and binding affinity of tropeines. Displacing potencies were also measured for [3H]granisetron binding to 5-HT3 type serotonin receptors of rat cerebral cortex. Selectivities to glycine receptors versus 5-HT3 receptors varied within 4 orders of magnitude. Nortropeines might serve as a lead to high-affinity selective allosteric modulators of glycine receptors.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm040814g