AMPA receptor positive allosteric modulators are positive allosteric modulators (PAMs) of the AMPA receptor (AMPR), a type of ionotropic glutamate receptor which mediates most fast synaptic neurotransmission in the central nervous system. [1]
AMPA receptor positive allosteric modulators are positive allosteric modulators (PAMs) of the AMPA receptor (AMPR), a type of ionotropic glutamate receptor which mediates most fast synaptic neurotransmission in the central nervous system. [1]
AMPAR PAMs have cognition- and memory-enhancing and antidepressant-like effects in preclinical models. It has potential medical applications in the treatment of cognitive impairment (e.g., cognitive symptoms in schizophrenia, mild cognitive impairment), dementia (e.g., Alzheimer's disease), depression, and for other indications. [1] [2] They can broadly be divided into low-impact and high-impact potentiators, with high-impact potentiators able to produce comparatively more robust increases in AMPAR activation. [3] However, high-impact AMPAR PAMs can cause motor coordination disruptions, convulsions, and neurotoxicity at sufficiently high doses, similarly to orthosteric AMPAR activators (i.e., active/glutamate site agonists). [2]
The AMPAR is one of the most highly expressed receptors in the brain, and is responsible for the majority of fast excitatory amino acid neurotransmission in the central nervous system (CNS). [4] Considering the broad impact of the AMPARs in the CNS, selectively targeting AMPARs involved in disease is difficult, and it is thought that global enhancement of AMPARs may be associated with an intolerable level of toxicity. [4] [1] For this reason, doubt has been cast on the feasibility of AMPAR activators for use in medicine. [1] However, low doses of AMPAR activators may nonetheless be useful, and AMPAR PAMs, which, unlike agonists, show selectivity for AMPAR subpopulations of different subunit compositions, may hold greater potential for medical applications. [4] [1]
AMPAR PAMs bind to one or more allosteric sites on the AMPAR complex and potentiate the receptor. [4] Unlike orthosteric (active/glutamate) site AMPAR activators, otherwise known as AMPAR agonists, AMPAR PAMs only potentiate AMPAR signaling in the presence of glutamate and hence do not activate the receptor directly/themselves. [4] Moreover, whereas AMPAR agonists activate all AMPARs, AMPAR PAMs can show selectivity for specific subpopulations of AMPARs. [4] This is because the AMPAR is composed of different combinations of various subunits, and the allosteric sites differ depending on the different subunit combinations. [4]
AMPAR PAMs can be broadly grouped into two types based on their binding site and impact on AMPAR activation: low-impact (type I) and high-impact (type II). [5] Low-impact AMPAR PAMs have the following criteria: [5]
While high-impact AMPAR PAMs have the following criteria: [5]
Low-impact AMPAR PAMs decrease AMPAR deactivation (channel closing) alone to augment synaptic currents while high-impact AMPAR PAMs decrease both deactivation and desensitization together to enhance and prolong synaptic currents. [3] Low-impact AMPAR PAMs have only slight effects on AMPAR currents, whereas high-impact AMPAR PAMs have effects more similar to those of AMPAR agonists and can produce strong enhancement. [6] [7] Similarly to AMPAR agonists, high-impact AMPAR PAMs can cause convulsions and neurotoxicity in sufficiently high doses. [2] Conversely, low-impact AMPAR PAMs have few adverse effects. [6]
There are several major chemical classes of AMPAR PAMs: [8] [4]
These classes have divergent properties, including allosteric site specificity, potency, impact (i.e., low versus high), and selectivity for AMPAR populations composed of different subunits. [8] [4] All of the biarylpropylsulfonamides are high-impact AMPAR PAMs, whereas the majority of the ampakines are low-impact AMPAR potentiators. [10] The biarylpropylsulfonamides are highly potent, on the order of 1,000-fold more potent than the ampakines and cyclothiazide. [10]
AMPAR PAMs can be broadly grouped by their impact on AMPAR activation: [5] [3] [11]
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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. The seedlings of these plants contain enzymes capable of complex chemical substitutions that result in the formation of free amino acids (See:#Synthesis). Willardiine is frequently studied for its function in higher level plants. Additionally, many derivates of willardiine are researched for their potential in pharmaceutical development. Willardiine was first discovered in 1959 by R. Gmelin, when he isolated several free, non-protein amino acids from Acacia willardiana (another name for Mariosousa willardiana) when he was studying how these families of plants synthesize uracilyalanines. A related compound, Isowillardiine, was concurrently isolated by a different group, and it was discovered that the two compounds had different structural and functional properties. Subsequent research on willardiine has focused on the functional significance of different substitutions at the nitrogen group and the development of analogs of willardiine with different pharmacokinetic properties. In general, Willardiine is the one of the first compounds studied in which slight changes to molecular structure result in compounds with significantly different pharmacokinetic properties.
Osavampator is an experimental drug being investigated as a treatment for treatment-resistant depression. It is being developed by Takeda Pharmaceuticals.
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