Willardiine (correctly spelled with two successive i's) or (S)-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione is a chemical compound that occurs naturally in the seeds of Mariosousa willardiana and Acacia sensu lato.

[1] The seedlings of these plants contain enzymes capable of complex chemical substitutions that result in the formation of free amino acids (See: #Synthesis).

Binding causes a conformational change that opens the receptor and allows for positively charged ions, Na+ and/or Ca2+ to enter the cell** (Figure 3).

The ion can also initiate a signaling cascade to activate different types of proteins that influence the cell, such as kinases or transcription factors.

The synthesis consists of a free uracil ring at nitrogen being substituted for an alanyl side chain, derived from O-acetyl-L-serine.

[2] The lower binding affinity of willardiine for the AMPA and kainate receptors can be attributed to the unsubstituted carbon on position 5 of the 6-membered ring.

[14] These antagonists have therapeutic potential for a variety of neurological disorders characterized by aberrant activation of AMPA or kainate receptors (See: #Disease relevance).

[6] These glutamate receptors are the primary mediators of excitation in the central nervous system, and are commonly studied in hippocampal or cortical neurons.

These crystallography studies were performed with a variety of 5-position halogen-substituted willardiine analogs to show that steric hindrance influences the extent of domain closure.

Thus, the synthetic UBP antagonists can be used to study the structural elements of each binding site that are important for activation or inhibition of the receptor based on the subunit.

[9] Calcium imaging in the presence of willardiine and related analogs could differentiate what receptor subtypes are activated by each agonist or inhibited by each antagonist.

Different doses and formulations of the compound will help identify potential therapeutic applications and any dose-dependent affects.

The aforementioned research could also help understand the potential application of willardiine and its more potent analogs and derived antagonists in treating neurological disease.

AMPA receptors have an extensive physiological role in synaptic plasticity, which is the basis for many aspects of neural development, learning, and memory.

Expression of mutant Huntingtin impairs AMPA-mediated synaptic transmission by disrupting subunit transport across microtubules.

[7] There are reports of genetic alterations in humans with autism spectrum disorders that result in hemizygosity of the GluA2 subunit, which is crucial for mediating calcium permeability of the AMPA receptor.

Human GRIP1, SHANK3 (as well as other members of the SHANK family), and E3 Ubiquitin Ligase all have identified mutations in Autism Spectrum Disorders that dysregulate AMPA synaptic expression.

In multiple retrospective cohort studies, it was found that adolescent patients of these diseases had significant, positive changes in social conduct, hyperactivity, and attention with minor side effects.

This result suggests a role of differentially expressed GluK4 in bipolar disorder and responses to medication, but research into the specific mechanism is still ongoing.

It is thought that the increase of kainate receptor activation causes the formation of aberrant synapses in the hippocampus and other areas that are considered to have a low epileptogenic threshold.

However, these varied and sometimes contradictory mechanisms of action showcase the numerous potentials of a kainate receptor therapeutic that can specifically target one brain region.

However, since willardiine has a low binding affinity as a partial agonist, it is not commonly studied as a potential therapeutic for diseases characterized by dysregulated receptor expression or activation.

AMPA agonists, and potentially willardiine analogs, are most commonly studied as treatments for Major depressive disorder (See: Disease relevance).

Willardiine-derived kainate antagonists have shown efficacy in treating pain, epilepsy, anxiety, ischemia and axonal degeneration.

One antagonist showed increased latency of escape in a hot plate test and decreased the amount of paw licking after exposure to a painful stimuli.

Inhibiting AMPA receptors can have severe toxic effects, such as dyskenesia and changes in mood caused by alterations in dopaminergic pathways.

[20] Thus, neither willardiine nor its analogs can be pursued as a therapeutic for any aforementioned neurological disorder until the toxicity and adverse effects of the compound are well characterized.

The research applications and potentials for therapeutics are numerous because of the varied role of non-NMDA glutamate receptors in disease.

For this reason, the extracellular levels of AMPA agonists (such as endogenous glutamate) are strictly controlled in the brain and spinal cord.

Analogs with higher binding affinity, such as 5-Fluorowillardiine, have been shown to induce seizure and cell death when administered at high doses.