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PF-04958242
Pesampator (; developmental code names BIIB-104 and PF-04958242) is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which is under development by Pfizer for the treatment of cognitive symptoms in schizophrenia. It was also under development for the treatment of age-related sensorineural hearing loss, but development for this indication was terminated due to insufficient effectiveness. As of July 2018, pesampator is in phase II clinical trials for cognitive symptoms in schizophrenia. Pesampator belongs to the biarylpropylsulfonamide group of AMPAR PAMs, which also includes LY-404187, LY-503430, and mibampator (LY-451395) among others. It is described as a "high-impact" AMPAR PAM, unlike so-called "low-impact" AMPAR PAMs like CX-516 and its cogener farampator (CX-691, ORG-24448). In animals, low doses of pesampator have been found to enhance cognition and memory, whereas higher doses produce motor coordination disruptio ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Biarylpropylsulfonamide
AMPA receptor positive allosteric modulators are positive allosteric modulators (PAMs) of the receptor (AMPR), a type of ionotropic glutamate receptor which mediates most fast synaptic neurotransmission in the central nervous system. Medical applications AMPAR PAMs have cognition- and memory-enhancing and antidepressant-like effects in preclinical models, and have 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. 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 disruptions, convulsions, and neurotoxicity at sufficiently high doses, similarly to orthosteric AMPAR activators (i.e., active/glutamate site agonists). The A ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
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 Alzheimer's disease but was never marketed. It reached phase II clinical trials prior to the discontinuation of its development. Mibampator belongs to the biarylpropylsulfonamide group of AMPAR PAMs, which also includes LY-404187, LY-503430, and PF-04958242 among others. It is a "high-impact" AMPAR potentiator, unlike "low-impact" AMPAR potentiators from other classes like CX-516 and its congener farampator (CX-691, ORG-24448), and is able to elicit comparatively more robust increases in AMPAR signaling. In animals, high-impact AMPAR potentiators enhance cognition and memory at low doses, but produce motor coordination disruptions, convulsions, and neurotoxicity at higher doses. Mibampator failed to produce cognitive improvement in pat ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
AMPA Receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synapse, synaptic transmission in the central nervous system (CNS). It has been traditionally classified as a non-NMDA_receptor, NMDA-type receptor, along with the kainate receptor. Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualic acid, quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. The ''GRIA2''-encoded AMPA receptor ligand binding core (GluA2 LBD) was the first glutamate receptor ion channel domain to be protein crystal, crystallized. Structure ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
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. Selective inhibitors Elevation of extracellular synaptic glycine concentration by blockade of GlyT1 has been hypothesized to potentiate NMDA receptor function in vivo and to represent a rational approach for the treatment of schizophrenia and cognitive disorders. Several drug candidates have reached clinical trials. * ASP2535 * Bitopertin (RG1678), which has entered phase II trials for the treatment of schizophrenia * Iclepertin ( BI 425809) by Boehringer Ingelheim which is thought to improve cognitive impairment due to schizophrenia * Org 25935 ORG-25935, also known as SCH-900435 is a synthetic drug developed by Organon International, which acts as a selective inhibitor of the glycine transporter GlyT-1. In animal tests it reduces alcohol consumption and has analgesic An analgesic ... (Sch 900435) * PF-03463275 (in p ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
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 in the intended movement. The modifications of these parameters typically relies on sensory feedback from one or more sensory modalities ( see: multisensory integration), such as proprioception and vision. Properties Large Degrees of Freedom Goal-directed and coordinated movement of body parts is inherently variable because there are many ways of coordinating body parts to achieve the intended movement goal. This is because the degrees of freedom (DOF) is large for most movements due to the many associated neuro-musculoskeletal elements.Bernstein N. (1967). The Coordination and Regulation of Movements. Pergamon Press. New York. Some examples of non-repeatable movements are when pointing or standing up from sitting. Complexity The complexi ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Motor Disorder
Motor disorders are disorders of the nervous system that cause abnormal and involuntary movements. They can result from damage to the motor system. Motor disorders are defined in the fifth edition of the ''Diagnostic and Statistical Manual of Mental Disorders'' (DSM-5) – published in 2013 to replace the fourth text revision (DSM-IV-TR) – as a new sub-category of neurodevelopmental disorders. The DSM-5 motor disorders include developmental coordination disorder, stereotypic movement disorder, and the tic disorders including Tourette syndrome. Signs and symptoms Motor disorders are malfunctions of the nervous system that cause involuntary or uncontrollable movements or actions of the body. These disorders can cause lack of intended movement or an excess of involuntary movement.Mandal, Ananya, MD. "What Are Movement Disorders?" News-Medical.net. AZO Network, 14 Oct. 2014. Web. 10 Nov. 2016. Symptoms of motor disorders include tremors, jerks, twitches, spasms, contractions, or ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
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 synonym for ''seizure''. However, not all epileptic seizures lead to convulsions, and not all convulsions are caused by epileptic seizures. Convulsions are also consistent with an electric shock and improper enriched air scuba diving. Non-epileptic convulsions have no relation with epilepsy, and are caused by non-epileptic seizures. Convulsion is a common term generally describing uncontrollable muscle contractions. The term convulsion has been used interchangeably with the word "seizure". Seizures may cause a person to have convulsions, but this is not always the case. Convulsion is a type of seizure that involves bursts of electrical activity in the brain. Occasionally the reason for a convulsion is unfamiliar. A convulsion may be caused ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
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 – specifically, a neurotoxin or neurotoxicant– alters the normal activity of the nervous system in such a way as to cause permanent or reversible damage to nervous tissue. This can eventually disrupt or even kill neurons, which are cells that transmit and process signals in the brain and other parts of the nervous system. Neurotoxicity can result from organ transplants, radiation treatment, certain drug therapies, recreational drug use, and exposure to heavy metals, bites from certain species of venomous snakes, pesticides, certain industrial cleaning solvents, fuels and certain naturally occurring substances. Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
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 (i.e., an ''allosteric site'') is not the same one to which an endogenous agonist of the receptor would bind (i.e., an ''orthosteric site''). Modulators and agonists can both be called receptor ligands. Allosteric modulators can be 1 of 3 types either: positive, negative or neutral. Positive types increase the response of the receptor by increasing the probability that an agonist will bind to a receptor (i.e. affinity), increasing its ability to activate the receptor (i.e. efficacy), or both. Negative types decrease the agonist affinity and/or efficacy. Neutral types don't affect agonist activity but can stop other modulators from binding to an allosteric site. Some modulators also work as allosteric agonists. The term "allosteric" derive ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Active Site
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) and residues that catalyse a reaction of that substrate (catalytic site). Although the active site occupies only ~10–20% of the volume of an enzyme, it is the most important part as it directly catalyzes the chemical reaction. It usually consists of three to four amino acids, while other amino acids within the protein are required to maintain the tertiary structure of the enzymes. Each active site is evolved to be optimised to bind a particular substrate and catalyse a particular reaction, resulting in high specificity. This specificity is determined by the arrangement of amino acids within the active site and the structure of the substrates. Sometimes enzymes also need to bind with some cofactors to fulfil their function. The active si ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
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, it would be impossible for language, relationships, or personal identity to develop. Memory loss is usually described as forgetfulness or amnesia. Memory is often understood as an informational processing system with explicit and implicit functioning that is made up of a sensory processor, short-term (or working) memory, and long-term memory. This can be related to the neuron. The sensory processor allows information from the outside world to be sensed in the form of chemical and physical stimuli and attended to various levels of focus and intent. Working memory serves as an encoding and retrieval processor. Information in the form of stimuli is encoded in accordance with explicit or implicit functions by the working memory processor. ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Ketamine
Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses neither respiration nor heart rate. Ketamine is also simple to administer and highly tolerable compared to drugs with similar effects which are flammable, irritating, or even explosive. Ketamine is a novel compound, derived from PCP, created in pursuit of a safer anesthetic with similar characteristics. Ketamine is also used for acute pain management. At anesthetic doses, ketamine induces a state of "dissociative anesthesia", a trance-like state providing pain relief, sedation, and amnesia. The distinguishing features of ketamine anesthesia are preserved breathing and airway reflexes, stimulated heart function with increased blood pressure, and moderate bronchodilation. At lower, sub-anesthetic doses, ketamine is a promising agent for pain ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
