(S)-Willardiine - CAS 21416-43-3
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Not Intended for Therapeutic Use. For research use only.
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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.
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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.
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CAS 21416-43-3 (S)-Willardiine

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