title: Assessment of structurally diverse philanthotoxin analogues for inhibitory activity on ionotropic glutamate receptor subtypes: discovery of nanomolar, nonselective, and use-dependent antagonists.
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.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Sidsel
authors.initials: S
authors.lastname: Frølund
authors.forename: Angelo
authors.initials: A
authors.lastname: Bella
authors.forename: Anders S
authors.initials: AS
authors.lastname: Kristensen
authors.forename: Hanne L
authors.initials: HL
authors.lastname: Ziegler
authors.forename: Matthias
authors.initials: M
authors.lastname: Witt
authors.forename: Christian A
authors.initials: CA
authors.lastname: Olsen
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
authors.forename: Henrik
authors.initials: H
authors.lastname: Franzyk
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Jaroszewski
mesh_terms: D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021122:Protein Subunits / Q000037:antagonists & inhibitors; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014862:Wasp Venoms / Q000737:chemistry*; D014982:Xenopus laevis
chemical_list: D018691:Excitatory Amino Acid Antagonists; D010636:Phenols; D011073:Polyamines; D021122:Protein Subunits; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D014862:Wasp Venoms; C074003:philanthotoxin 343; C034092:delta-philanthotoxin