(S)-Willardiine - CAS 21416-43-3
Catalog number: 21416-43-3
Category: Inhibitor
Please be kindly noted products are not for therapeutic use. We do not sell to patients.
Molecular Formula:
C7H9N3O4
Molecular Weight:
199.16
COA:
Inquire
Targets:
AMPAR
Description:
The (S)- but not (R)-isomers of willardiine and 5-bromowillardiine were potent agonists, producing rapidly but incompletely desensitizing responses. At a concentration of 1.8 mM, Ca2+ inhibited the currents induced by 100 microM willardiine by approximately 50%. In newborn mice (P5, histopathology at P10), local injection of the AMPA receptor agonist S-bromo-willardiine at day 5 after birth induced cortical damage and white matter damage, which was reduced in a dose-dependent manner by the AMPA receptor antagonists.
Purity:
>98%
Synonyms:
(-)-Willardiine
MSDS:
Inquire
InChIKey:
FACUYWPMDKTVFU-BYPYZUCNSA-N
InChI:
InChI=1S/C7H9N3O4/c8-4(6(12)13)3-10-2-1-5(11)9-7(10)14/h1-2,4H,3,8H2,(H,12,13)(H,9,11,14)/t4-/m0/s1
Canonical SMILES:
C1=CN(C(=O)NC1=O)CC(C(=O)O)N
1.A quantum biochemistry investigation of willardiine partial agonism in AMPA receptors.
Lima Neto JX1, Fulco UL, Albuquerque EL, Corso G, Bezerra EM, Caetano EW, da Costa RF, Freire VN. Phys Chem Chem Phys. 2015 May 21;17(19):13092-103. doi: 10.1039/c4cp05630b.
We employ quantum biochemistry methods based on the Density Functional Theory (DFT) approach to unveil the detailed binding energy features of willardiines co-crystallized with the AMPA receptor. Our computational results demonstrate that the total binding energies of fluorine-willardiine (FW), hydrogen-willardiine (HW), bromine-willardiine (BrW) and iodine-willardiine (IW) to the iGluR2 ligand-pocket correlate with the agonist binding energies, whose experimental sequential data match our computational counterpart, excluding the HW case. We find that the main contributions to the total willardiine-iGluR2 binding energy are due to the amino acid residues in decreasing order Glu705 > Arg485 > Ser654 > Tyr450 > T655. Furthermore, Met708, which is positioned close to the 5-substituent, attracts HW and FW, but repels BrW and IW. Our results contribute significantly to an improved understanding of the willardiine-iGluR2 binding mechanisms.
2.Mechanisms of antagonism of the GluR2 AMPA receptor: structure and dynamics of the complex of two willardiine antagonists with the glutamate binding domain.
Ahmed AH1, Thompson MD, Fenwick MK, Romero B, Loh AP, Jane DE, Sondermann H, Oswald RE. Biochemistry. 2009 May 12;48(18):3894-903. doi: 10.1021/bi900107m.
Ionotropic glutamate receptors mediate the majority of vertebrate excitatory synaptic transmission. The development of selective antagonists for glutamate receptor subtypes is of interest in the treatment of a variety of neurological disorders. This study presents the crystal structure of the binding domain of GluR2 bound to two antagonists (UBP277 and UBP282) that are derivatives of the natural product, willardiine. The antagonists bind to one lobe of the protein with interactions similar to agonists. Interaction with the second lobe differs between the two antagonists, resulting in a different position of the uracil ring and different orientations of the bilobed structure. UBP277 binding produces a stable lobe orientation that is similar to the apo state, but the binding of UBP282 produces the largest hyperextension of the lobes yet reported for an AMPA receptor. The carboxyethyl (UBP277) and carboxybenzyl (UBP282) substituents in the N(3) position keep the lobes separated by a "foot-in-the-door" mechanism and the internal dynamics are minimal compared to the CNQX-bound form of the protein (which makes minimal contacts with one of the two lobes).
3.Thermodynamics and mechanism of the interaction of willardiine partial agonists with a glutamate receptor: implications for drug development.
Martinez M1, Ahmed AH, Loh AP, Oswald RE. Biochemistry. 2014 Jun 17;53(23):3790-5. doi: 10.1021/bi500511m. Epub 2014 Jun 5.
Understanding the thermodynamics of binding of a lead compound to a receptor can provide valuable information for drug design. The binding of compounds, particularly partial agonists, to subtypes of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor is, in some cases, driven by increases in entropy. Using a series of partial agonists based on the structure of the natural product, willardiine, we show that the charged state of the ligand determines the enthalpic contribution to binding. Willardiines have uracil rings with pKa values ranging from 5.5 to 10. The binding of the charged form is largely driven by enthalpy, while that of the uncharged form is largely driven by entropy. This is due at least in part to changes in the hydrogen bonding network within the binding site involving one water molecule. This work illustrates the importance of charge to the thermodynamics of binding of agonists and antagonists to AMPA receptors and provides clues for further drug discovery.
Molecular Weight Calculator Molarity Calculator Solution Dilution Calculator

Related AMPAR Products


CAS 380607-77-2 CMPDA

CMPDA
(CAS: 380607-77-2)

CMPDA is a positive allosteric modulator of AMPA receptors. Binds at the modulator binding pocket located at the interdimer interface and the clamshell hinges.

CAS 72432-10-1 Aniracetam

Aniracetam
(CAS: 72432-10-1)

Aniracetam is a nootropics and neuroprotective drug.

CAS 211311-95-4 LY 404187

LY 404187
(CAS: 211311-95-4)

LY 404187 is an allosteric modulator of AMPA receptors (IC50 = 0.15μM, 0.21μM, 1.66μM and 5.65 μM for GluA2i, GluA4i, GluA3i and GluA1i, respectively).

CAS 122306-11-0 Naspm

Naspm
(CAS: 122306-11-0)

A poliamine amide as potent Spermidine uptake inhibitor.

CAS 1257323-84-4 NPEC-caged-(S)-AMPA

NPEC-caged-(S)-AMPA
(CAS: 1257323-84-4)

A caged version of (S)-AMPA. (S)-AMPA is an AMPA receptor agonist.

CAS 157115-85-0 Noopept

Noopept
(CAS: 157115-85-0)

Noopept is a nootropic and neuroprotective drug that normalizes the balance of the pro- and antioxidant systems. Noopept modulates a variety of physiological fu...

CAS 171259-81-7 (RS)-AMPA hydrobromide

(RS)-AMPA hydrobromide
(CAS: 171259-81-7)

The hydrobromide salt form of (RS)-AMPA, which has been found to be an agonist of the excitatory neurotransmitter L-glutamic Acid.

CAS 215923-54-9 CX546

CX546
(CAS: 215923-54-9)

It is one of a series of AMPA modulators for the potential treatment of Alzheimer's disease, schizophrenia, and mild cognitive impairment (MCI). An ampakine dru...

Chemical Structure

CAS 21416-43-3 (S)-Willardiine

Quick Inquiry

Verification code

Featured Items