Pesampator (; developmental code names BIIB-104 and PF-04958242) is a

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 stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that ...

(PAM) of the

AMPA receptor The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic glutamate receptor (iGluR) and predominantly sodium ion channel that mediates fast excitator ...

(AMPAR), an

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 was under development by

Pfizer Pfizer Inc. ( ) is an American Multinational corporation, multinational Pharmaceutical industry, pharmaceutical and biotechnology corporation headquartered at The Spiral (New York City), The Spiral in Manhattan, New York City. Founded in 184 ...

for the treatment of cognitive symptoms in

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

. In March 2018, the development of the drug was transferred over from Pfizer to

Biogen Biogen Inc. is an American multinational biotechnology company based in Cambridge, Massachusetts, United States specializing in the discovery, development, and delivery of the treatment of neurological diseases to patients worldwide. Biogen ope ...

. It was also under development for the treatment of age-related

sensorineural hearing loss Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear, sensory organ (cochlea and associated structures), or the vestibulocochlear nerve (Cranial nerves, cranial nerve VIII). SNHL accounts for a ...

, but development for this indication was terminated due to insufficient effectiveness. In July 2022, Biogen discontinued the development of pesampator for cognitive symptoms in schizophrenia due to ineffectiveness. Pesampator belongs to the

biarylpropylsulfonamide AMPA receptor positive allosteric modulators are positive allosteric modulators (PAMs) of the AMPA receptor, receptor (AMPR), a type of ionotropic glutamate receptor which mediates most fast synaptic cleft, synaptic neurotransmission in the cen ...

group of AMPAR PAMs, which also includes

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-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 neuro ...

, and

mibampator Mibampator (developmental code name LY-451395) is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which was under development by Eli Lilly for the treatment of agitation/aggression in Alzhei ...

(LY-451395) among others. It is described as a "high-impact" AMPAR PAM, unlike so-called "low-impact" AMPAR PAMs like

CX-516 CX-516 is an ampakine and nootropic that acts as an AMPA receptor positive allosteric modulator and had been undergoing development by a collaboration between Cortex, Shire, and Servier. It was studied as a potential treatment for Alzheimer's d ...

and its congener

farampator Farampator (developmental code names CX-691, ORG-24448, SCH-900460) is an ampakine drug. It was developed by Cortex Pharmaceuticals, and licensed to Organon BioSciences for commercial development. Following the purchase of Organon by Schering-P ...

(CX-691, ORG-24448). In animals, low doses of pesampator have been found to enhance

cognition Cognition is 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, thought, ...

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 remembe ...

, whereas higher doses produce

motor coordination In physiology, 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 bo ...

disruptions and

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 often used as a synony ...

s. The same effects, as well as

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 higher doses, have been observed with

orthosteric In the fields of biochemistry and pharmacology an allosteric regulator (or allosteric modulator) is a substance that binds to a site on an enzyme or receptor distinct from the active site, resulting in a conformational change that alters the p ...

and other high-impact

allosteric In the fields of biochemistry and pharmacology an allosteric regulator (or allosteric modulator) is a substance that binds to a site on an enzyme or receptor distinct from the active site, resulting in a conformational change that alters the p ...

AMPAR activators. In healthy volunteers, pesampator has been found to significantly reduce

ketamine Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...

-induced deficits in

verbal learning Learning is the process of acquiring new understanding, knowledge, behaviors, skills, values, attitudes, and preferences. The ability to learn is possessed by humans, non-human animals, and some machines; there is also evidence for some kind ...

and

working memory Working memory is a cognitive system with a limited capacity that can Memory, hold information temporarily. It is important for reasoning and the guidance of decision-making and behavior. Working memory is often used synonymously with short-term m ...

without attenuating ketamine-induced

psychotomimetic A drug with psychotomimetic (also known as psychomimetic or psychotogenic) actions mimics the symptoms of psychosis, including delusions and/or delirium, as opposed to only hallucinations. Psychotomimesis is the onset of psychotic symptoms followi ...

effects. It was able to complete reverse ketamine-induced impairments in

spatial working memory In cognitive psychology and neuroscience, spatial memory is a form of memory responsible for the recording and recovery of information needed to plan a course to a location and to recall the location of an object or the occurrence of an event. Sp ...

in the participants. In addition to its actions on the AMPAR, pesampator has been reported to act as a

GlyT1 Sodium- and chloride-dependent glycine transporter 1, also known as glycine transporter 1, is a protein that in humans is encoded by the ''SLC6A9'' gene which is promising therapeutic target for treatment of diabetes and obesity. Selective inhi ...

glycine transporter Glycine transporters (GlyTs) are plasmalemmal neurotransmitter transporters. They serve to terminate the signaling of glycine by mediating its reuptake from the synaptic cleft back into the presynaptic neurons. There are two glycine transporters: ...

blocker. As such, it is also a

glycine reuptake inhibitor A glycine reuptake inhibitor (GRI) is a type of drug which inhibits the reuptake of the neurotransmitter glycine by blocking one or more of the glycine transporters (GlyTs). Examples of GRIs include bitopertin (RG1678), iclepertin (BI-425809), ...

, and may act indirectly to activate the

glycine receptor The glycine receptor (abbreviated as GlyR or GLR) is the receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochem ...

and the

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...

co-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 agoni ...

site Site most often refers to: * Archaeological site * Campsite, a place used for overnight stay in an outdoor area * Construction site * Location, a point or an area on the Earth's surface or elsewhere * Website, a set of related web pages, typical ...

of the

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...

by increasing

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

levels of

References

{{Ionotropic glutamate receptor modulators AMPA receptor positive allosteric modulators Experimental drugs Glycine reuptake inhibitors Nitriles Nootropics Sulfonamides Tetrahydrofurans Thiophenes

See also

References