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RTI-7470-44
RTI-7470-44 is a potent and selective antagonist of the human trace amine-associated receptor 1 (TAAR1) which is used in scientific research. It was discovered in 2022 and is the first potent antagonist of the human TAAR1 to be identified, following the potent mouse TAAR1 inverse agonist EPPTB in 2009. Pharmacology The affinity (Ki) of RTI-7470-44 for the human TAAR1 is 0.3nM and its inhibitory potency () at the receptor is 8.4nM ''in vitro''. It is about 90-fold less potent at the rat TAAR1 ( = 748nM) and 140-fold less potent at the mouse TAAR1 ( = 1,190nM) compared to the human TAAR1. Surprisingly, RTI-7470-44 was found to be a competitive antagonist of the human and mouse TAAR1 but a non-competitive antagonist of the rat TAAR1. The compound has favorable ''in vivo'' drug-like properties, including good blood–brain barrier permeability, moderate metabolic stability, and a favorable preliminary profile of off-target activity (≥1–10μM at 42other targets). It is far m ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
EPPTB
EPPTB, also known as RO5212773 or RO-5212773, is a drug developed by Hoffmann-La Roche which acts as a potent and selective antagonist or inverse agonist of the trace amine-associated receptor 1 (TAAR1). The drug was the first selective antagonist developed for the TAAR1. It is a potent agonist of the mouse and rat TAAR1, but is dramatically less potent as an agonist of the human TAAR1. EPPTB has been used in scientific research to demonstrate an important role for TAAR1 in regulation of dopaminergic signaling in the limbic system. Pharmacology Pharmacodynamics Actions EPPTB acts as a potent and selective trace amine-associated receptor 1 (TAAR1) full antagonist. Although EPPTB has high affinity for the mouse TAAR1 (mTAAR1) (Ki = 0.9nM), it has much lower affinity for rat TAAR1 (rTAAR1) (Ki = 942nM) and human TAAR1 (hTAAR1) (Ki = >5,000nM), which limits its use in research. While the mTAAR1 and hTAAR1 have similar functions and bind similar ligands, the actual binding affinit ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Trace Amine-associated Receptor 1
Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is a primarily intracellular amine-activated and G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells (e.g., the stomach, small intestine, duodenum, and white blood cells), astrocytes, and in the intracellular milieu within the presynaptic plasma membrane (i.e., axon terminal) of monoamine neurons in the central nervous system (CNS). TAAR1 is one of six functional human TAARs, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS; it also affects immune system and neuroimmune system function through different mechanisms. Endogenous ligands of the TAAR1 include trace amines, monoamine neurotransmitter ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
RO5166017
RO5166017, or RO-5166017, is a drug developed by Hoffmann-La Roche which acts as a potent and selective agonist for the trace amine-associated receptor 1 (TAAR1), with no significant activity at other targets. It is a partial agonist or near-full agonist depending on the species. The drug is important for the study of the TAAR1 receptor, as while numerous other compounds are known which act as TAAR1 agonists, such as methamphetamine, MDMA, and 3-iodothyronamine, all previously known TAAR1 agonists are either weak and rapidly metabolized (endogenous ligands), or have strong pharmacological activity at other targets (amphetamines, thyronamines), making it very difficult to assess which effects are due to TAAR1 activation. The discovery of RO-5166017 allows purely TAAR1 mediated effects to be studied. Pharmacology Pharmacodynamics Actions RO5166017 is a partial agonist or near-full agonist of the TAAR1 depending on the species examined. Its values are 3.3 to 8.0nM for the mouse ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Blood–brain Barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system, thus protecting the brain from harmful or unwanted substances in the blood. The blood–brain barrier is formed by endothelial cells of the Capillary, capillary wall, astrocyte end-feet ensheathing the capillary, and pericytes embedded in the capillary basement membrane. This system allows the passage of some small molecules by passive transport, passive diffusion, as well as the selective and active transport of various nutrients, ions, organic anions, and macromolecules such as glucose and amino acids that are crucial to neural function. The blood–brain barrier restricts the passage of pathogens, the diffusion of solutes in the blood, and Molecular mass, large or Hydrophile, hydrophilic molecules into the cerebrospinal fluid, while a ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Partial Agonist
In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (biochemistry), ligands which display both agonistic and Receptor antagonist, antagonistic effects—when both a full agonist and partial agonist are present, the partial agonist actually acts as a competitive antagonist, competing with the full agonist for receptor occupancy and producing a net decrease in the receptor activation observed with the full agonist alone. Clinically, partial agonists can be used to activate receptors to give a desired submaximal response when inadequate amounts of the endogenous ligand are present, or they can reduce the overstimulation of receptors when excess amounts of the endogenous ligand are present. Some currently common drugs that have been classed as partial agonists at particular receptors include buspi ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Maximal Efficacy
Intrinsic activity (IA) and efficacy (Emax) refer to the relative ability of a drug-receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind to its molecular target, and the EC50, which is a measure of the potency of the drug and which is proportional to both efficacy and affinity. This use of the word "efficacy" was introduced by Stephenson (1956) to describe the way in which agonists vary in the response they produce, even when they occupy the same number of receptors. High efficacy agonists can produce the maximal response of the receptor system while occupying a relatively low proportion of the receptors in that system. There is a distinction between efficacy and intrinsic activity. Mechanism of efficacy Agonists of lower efficacy are not as efficient at producing a response from the drug-bound receptor, by stabilizing the active form of the drug-bound receptor. Therefore, ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Ex Vivo
refers to biological studies involving tissues, organs, or cells maintained outside their native organism under controlled laboratory conditions. By carefully managing factors such as temperature, oxygenation, nutrient delivery, and perfusing a nutrient solution through the tissue's vasculature, researchers sustain function long enough to conduct experiments that would be difficult or unethical in a living body. ''Exvivo'' models occupy a middle ground between '' in vitro'' () models, which typically use isolated cells, and '' in vivo'' () studies conducted inside living organisms, offering both experimental control and physiological relevance. ''Ex vivo'' platforms support pharmacologic screening, toxicology testing, transplant evaluation, developmental biology, and investigations of disease-mechanism research across medicine and biology, from cardiology and neuroscience to dermatology and orthopedics. Because they often use human tissues obtained from clinical ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Slice Preparation
The slice preparation or brain slice is a laboratory technique in electrophysiology that allows the study of neurons from various brain regions in isolation from the rest of the brain, in an ex-vivo condition. Brain tissue is initially sliced via a tissue slicer then immersed in artificial cerebrospinal fluid (aCSF) for stimulation and/or recording. The technique allows for greater scientific control, experimental control, through elimination of the effects of the rest of the brain on the neural circuit, circuit of interest, careful control of the physiological conditions through perfusion of substrates through the incubation fluid, to precise manipulation of neurotransmitter activity through perfusion of agonists and antagonists. However, the increase in control comes with a decrease in the ease with which the results can be applied to the whole neural system. Slice preparation techniques Free hand sectioning is a type of preparation techniques where a skilled operator uses razo ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Ventral Tegmental Area
The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the origin of the dopaminergic cell bodies of the mesocorticolimbic dopamine system and other dopamine pathways; it is widely implicated in the drug and natural reward circuitry of the brain. The VTA plays an important role in a number of processes, including reward cognition ( motivational salience, associative learning, and positively-valenced emotions) and orgasm, among others, as well as several psychiatric disorders. Neurons in the VTA project to numerous areas of the brain, ranging from the prefrontal cortex to the caudal brainstem and several regions in between. Structure Neurobiologists have often had great difficulty distinguishing the VTA in humans and other primate brains from the substantia nigra (SN) and surrounding nuc ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Neuron
A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural network in the nervous system. They are located in the nervous system and help to receive and conduct impulses. Neurons communicate with other cells via synapses, which are specialized connections that commonly use minute amounts of chemical neurotransmitters to pass the electric signal from the presynaptic neuron to the target cell through the synaptic gap. Neurons are the main components of nervous tissue in all Animalia, animals except sponges and placozoans. Plants and fungi do not have nerve cells. Molecular evidence suggests that the ability to generate electric signals first appeared in evolution some 700 to 800 million years ago, during the Tonian period. Predecessors of neurons were the peptidergic secretory cells. They eventually ga ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Dopaminergic
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facilitate dopamine-related activity. For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors can be classified as dopaminergic, and neurons that Biosynthesis, synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as ''dopaminergic''. Enzymes that regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase or DOPA decarboxylase, monoamine oxidase (MAO), and catechol-O-methyl transferase, catechol ''O''-methyl transferase (COMT) may be referred to as ''dopaminergic'' as well. Also, any endogenous or exogenous chemical substance that acts to affect dopamine receptors or dopamine release thro ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
