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Assessment of structurally diverse philanthotoxin analogues for inhibitory activity on ionotropic glutamate receptor subtypes: discovery of nanomolar, nonselective, and use-dependent antagonists.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2010 Oct 28; Vol. 53 (20), pp. 7441-51. - Publication Year :
- 2010
-
Abstract
- An array of analogues of the wasp toxin philanthotoxin-433, in which the asymmetric polyamine moiety was exchanged for spermine and the headgroup replaced with a variety of structurally diverse moieties, was prepared using parallel solid-phase synthesis approaches. In three analogues, the spermine moiety was extended with an amino acid tail, six compounds contained an N-acylated cyclohexylalanine, and four analogues were based on a novel diamino acid design with systematically changed spacer length between N-cyclohexylcarbonyl and N-phenylacetyl substituents. The analogues were studied using two-electrode voltage-clamp electrophysiology employing Xenopus laevis oocytes expressing GluA1(i) AMPA or GluN1/2A NMDA receptors. Several of the analogues showed significantly increased inhibition of the GluN1/2A NMDA receptor. Thus, an analogue containing N-(1-naphtyl)acetyl group showed an IC(50) value of 47 nM. For the diamino acid-based analogues, the optimal spacer length between two N-acyl groups was determined, resulting in an analogue with an IC(50) value of 106 nM.
- Subjects :
- Animals
Excitatory Amino Acid Antagonists chemistry
Excitatory Amino Acid Antagonists pharmacology
Female
Oocytes drug effects
Oocytes physiology
Patch-Clamp Techniques
Phenols chemistry
Phenols pharmacology
Polyamines chemistry
Polyamines pharmacology
Protein Subunits antagonists & inhibitors
Structure-Activity Relationship
Xenopus laevis
Excitatory Amino Acid Antagonists chemical synthesis
Phenols chemical synthesis
Polyamines chemical synthesis
Receptors, AMPA antagonists & inhibitors
Receptors, N-Methyl-D-Aspartate antagonists & inhibitors
Wasp Venoms chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 53
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20873775
- Full Text :
- https://doi.org/10.1021/jm100886h