AMPA receptor positive allosteric modulators are

positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds to ...

s (PAMs) of the receptor (AMPR), a type of

ionotropic glutamate receptor Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are activated by the neurotransmitter glutamate. They mediate the majority of excitatory synaptic transmission throughout the central nervous system and are key players in ...

which mediates most fast synaptic

neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...

in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

Medical applications

AMPAR PAMs have

cognition Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thoug ...

- and

memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered ...

-enhancing and

antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness ...

-like effects in

preclinical model In drug development, preclinical development, also termed preclinical studies or nonclinical studies, is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and dr ...

s, and have potential medical applications in the treatment of

cognitive impairment Cognitive deficit is an inclusive term to describe any characteristic that acts as a barrier to the cognition process. The term may describe * deficits in overall intelligence (as with intellectual disabilities), * specific and restricted defic ...

(e.g., cognitive symptoms in

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wi ...

mild cognitive impairment Mild cognitive impairment (MCI) is a neurocognitive disorder which involves cognitive impairments beyond those expected based on an individual's age and education but which are not significant enough to interfere with instrumental activities of ...

dementia Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...

(e.g., Alzheimer's disease), depression, and for other indications. 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. However, high-impact AMPAR PAMs can cause

motor coordination Motor coordination is the orchestrated movement of multiple body parts as required to accomplish intended actions, like walking. This coordination is achieved by adjusting kinematic and kinetic parameters associated with each body part involved i ...

disruptions,

convulsion A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a ...

s, and

neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...

at sufficiently high doses, similarly to orthosteric AMPAR activators (i.e., active/glutamate site

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

s). The AMPAR is one of the most highly expressed receptors in the

brain The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head ( cephalization), usually near organs for special ...

, and is responsible for the majority of fast excitatory amino acid

in the

(CNS). 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 Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...

. For this reason, doubt has been cast on the feasibility of AMPAR activators for use in medicine. 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.

Pharmacology

AMPAR PAMs bind to one or more

allosteric site In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site. The site to which the effector binds is termed the ''allosteric sit ...

s on the AMPAR complex and potentiate the receptor. 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. Moreover, whereas AMPAR agonists activate all AMPARs, AMPAR PAMs can show selectivity for specific subpopulations of AMPARs. This is because the AMPAR is composed of different combinations of various subunits, and the allosteric sites differ depending on the different subunit combinations. 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). Low-impact AMPAR PAMs have the following criteria: * Have little or no effect on the half-width of the field excitatory postsynaptic potential (fEPSP); and * Do not substantially bind to the cyclothiazide site on the AMPAR complex; and * Do not induce the expression of

brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canon ...

(BDNF) While high-impact AMPAR PAMs have the following criteria: * Substantially alter/increase the half-width of the fEPSP; and/or * Substantially bind to the cyclothiazide site on the AMPAR complex; and * Induce the expression of BDNF 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. 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. Similarly to AMPAR agonists, high-impact AMPAR PAMs can cause convulsions and neurotoxicity in sufficiently high doses. Conversely, low-impact AMPAR PAMs have few

adverse effect An adverse effect is an undesired harmful effect resulting from a Pharmaceutical drug, medication or other Surgery#Definitions, intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main ...

Classes and list of drugs

By chemical structure

There are several major

chemical class Chemical classification systems attempt to classify elements or compounds according to certain chemical functional or structural properties. Whereas the structural properties are largely intrinsic, functional properties and the derived classifica ...

es of AMPAR PAMs: *

Benzamide Benzamide is a organic compound with the chemical formula of C6H5C(O)NH2. It is the simplest amide derivative of benzoic acid. In powdered form, it appears as a white solid, while in crystalline form, it appears as colourless crystals. It is slig ...

and related compounds (also known as

ampakine Ampakines, also stylized as AMPAkines, are a subgroup of AMPA receptor positive allosteric modulators with a benzamide or closely related chemical structure. They are also known as "CX compounds". Ampakines take their name from the AMPA recepto ...

s or CX compounds; mostly benzoylpyrrolidines) – 1-BCP (BA-14), CX-516 (Ampalex, BDP-12, BA-74, ORG-24292, SPD-420), CX-546, CX-554 (BDP-20), CX-614, farampator (CX-691, ORG-24481, SCH-900460), CX-717, CX-929, CX-1501, tulrampator (S-47445, CX-1632), CX-1739, CX-1796, CX-1837, CX-1942, CX-2007, CX-2076, ORG-26576, S-70340 * Benzothiadiazides – BIIR-777, cyclothiazide, diazoxide,

hydrochlorothiazide Hydrochlorothiazide is a diuretic medication often used to treat high blood pressure and swelling due to fluid build-up. Other uses include treating diabetes insipidus and renal tubular acidosis and to decrease the risk of kidney stones in th ...

(HCTZ),

IDRA-21 IDRA-21 is a positive allosteric modulator of the AMPA receptor and a benzothiadiazine derivative. It is a chiral molecule, with (+)-IDRA-21 being the active form. IDRA-21 shows nootropic effects in animal studies, significantly improving learni ...

, S-18986 * Biarylpropylsulfonamides and related compounds – LY-392098,

LY-404187 LY-404187 is an AMPA receptor positive allosteric modulator which was developed by Eli Lilly and Company. It is a member of the biarylpropylsulfonamide class of AMPA receptor potentiators. LY-404187 has been demonstrated to enhance cognitive fu ...

, LY-450108, mibampator (LY-451395), LY-4516146,

LY-503430 LY-503430 is an AMPA receptor positive allosteric modulator developed by Eli Lilly. LY-503430 produces both nootropic and neuroprotective effects, reducing brain damage caused by 6-hydroxydopamine or MPTP and also increasing levels of the neur ...

, PEPA, PF-04778574, pesampator (BIIB-104; PF-04958242), CMPDA, CMPDB, (''R'',''R'')-PIMSD *

Racetam Racetams are a class of drugs that share a pyrrolidone nucleus. Some, such as piracetam, aniracetam, oxiracetam, pramiracetam and phenylpiracetam are considered nootropics. Others such as levetiracetam, brivaracetam, and seletracetam are a ...

and related compounds (very weak) –

aniracetam Aniracetam (brand names Draganon, Sarpul, Ampamet, Memodrin, Referan), also known as ''N''-anisoyl-2-pyrrolidinone, is a racetam which is sold in Europe as a prescription drug. It is not approved by the Food and Drug Administration for use in th ...

piracetam Piracetam is a drug marketed as a treatment for myoclonus. It is also used as a cognitive enhancer to improve memory, attention, and learning. Evidence to support its use is unclear, with some studies showing modest benefits in specific populati ...

, various others * Others: PF-04701475, pesampator (BIIB-104; PF-04958242), GVS-111 These classes have divergent properties, including

specificity, potency, impact (i.e., low versus high), and selectivity for AMPAR populations composed of different subunits. All of the biarylpropylsulfonamides are high-impact AMPAR PAMs, whereas the majority of the ampakines are low-impact AMPAR potentiators. The biarylpropylsulfonamides are highly potent, on the order of 1,000-fold more potent than the ampakines and cyclothiazide.

By impact

AMPAR PAMs can be broadly grouped by their impact on AMPAR activation: * Low-impact (type I):

, CX-516 (Ampalex, BDP-12, BA-74, ORG-24292, SPD-420), CX-614, CX-717, CX-929, CX-1739, farampator (CX-691, ORG-24481, SCH-900460), ORG-24448,

* High-impact (type II): CX-701, CX-1837, CX-1846,

, LY-451646, mibampator (LY-451395), ORG-26576, pesampator (BIIB-104; PF-04958242), PF-4778574, tulrampator (S-47445, CX-1632)

References