5′-Alkyl-benzothiadiazides: A New Subgroup of AMPA Receptor Modulators with Improved Affinity
| Autor: | Dean Phillips, Rishi G. Vaswani, A. Richard Chamberlin, Markus Kessler, Thomas Kleisli, Amy C. Arai, Gary Lynch, Richard Granger, Jennifer Sonnenberg, Peter O. Krutzik |
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| Rok vydání: | 2002 |
| Předmět: |
Agonist
Patch-Clamp Techniques medicine.drug_class Clinical Biochemistry Pharmaceutical Science AMPA receptor Neurotransmission Benzothiadiazines Biochemistry Rats Sprague-Dawley Structure-Activity Relationship Drug Discovery medicine Animals Combinatorial Chemistry Techniques Potency Receptors AMPA Binding site Receptor Molecular Biology Neurons Sulfonamides Chemistry Organic Chemistry Glutamate receptor Brain Rats Kinetics Molecular Medicine Cyclothiazide Protein Binding medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 10:1229-1248 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/s0968-0896(01)00405-9 |
| Popis: | AMPA receptors form a major subdivision of the glutamate receptor family that mediates excitatory synaptic transmission in the brain. Currents through AMPA receptors can be up- or down-regulated by compounds that allosterically modulate receptor kinetics through binding sites distinct from that for glutamate. One of those modulators is the benzothiadiazide IDRA-21 which has been reported to enhance synaptic transmission and be effective in behavioral tests, but typically requires threshold concentrations of at least 100 microM to be active in vitro. In this study, new benzothiadiazides were developed with IDRA-21 as lead compound and examined for their potency in modulating AMPA receptor kinetics. A significant increase in drug affinity was obtained by alkyl substitution at the 5'-position of IDRA-21; substitutions at other positions of the benzothiadiazide core generally did not yield a further gain in affinity and in some cases abolished drug binding. The 5'-ethyl derivative exhibited an EC(50) value in the order of 22 microM which represents about a 30-fold gain in affinity over that of IDRA-21. The EC(50) value is comparable to that of cyclothiazide, the most potent benzothiadiazide drug, but the effects on AMPA receptors differed substantially between these two compounds in that the 5'-ethyl derivative of IDRA-21 greatly increased the binding affinity for receptor agonists whereas cyclothiazide is known to reduce agonist binding. The structure--activity relationships reported here thus offer to provide new insights how receptor kinetics is linked to particular aspects of receptor--drug interactions. |
| Databáze: | OpenAIRE |
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