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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
At their site of action, drugs interact with molecules termed drug ‘receptors’ or ‘targets’. These are often actual biological receptors, such as hormone receptors, but they may also be any other type of molecule, such as an enzyme or membrane channel. The affinity of a drug-receptor interaction is a measure of how tightly the two molecules bind. An agonist is a substance that has an effect on a specific drug receptor, causing activation of the function of the receptor molecule. A partial agonist has the same type of effect on the function of the receptor molecule, but even at the maximal effect of the drug, the function of the receptor molecule is not activated to its maximal level. An antagonist is a drug that binds, to but opposes, the natural activity of the receptor molecule. Competitive antagonists compete with agonists for the same receptor, but they do not exert an agonist effect themselves and so reduce the effect of any agonist present. In these circumstances, the overall effect will depend on the relative concentrations of agonist and antagonist. A non-competitive antagonist does not compete for the same site but opposes the effect of the agonist by another mechanism. Finally, an irreversible antagonist is an antagonist that inactivates the receptor molecule permanently once it has bound. This effect cannot be reversed, even at high concentration of agonist. Many drug receptors are bound by naturally occurring agonists and antagonists, including hormones and neurotransmitters.
The Neuromuscular Junction
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
Antagonists of a given neurotransmitter, also referred to sometimes as blockers, are substances that bind to the receptor of the neurotransmitter but reduce or block its action. Antagonists could be competitive, noncompetitive, or uncompetitive. As its name implies, a competitive antagonist competes with the neurotransmitter or agonist for the receptor sites. The binding of the competitive antagonist to the receptor site could be reversible (or surmountable), or it could be irreversible (or insurmountable). In the case of a reversible competitive antagonist, the bond to the receptor site is chemically reversible, so that the blocking action depends on the concentration of the antagonist and is reduced by a higher concentration of the neurotransmitter. On the other hand, increasing the concentration of the neurotransmitter does not reduce the blocking effect of an irreversible competitive antagonist that has bound to the site because the bond of the antagonist to the receptor site is chemically irreversible.
Toxicology
Published in Aruna Bakhru, Nutrition and Integrative Medicine, 2018
The action of the drug depends on whether it occupies the most receptors. For example, naloxone is a competitive antagonist for mu receptors and may be used to treat opioid overdose. It will compete with morphine for mu receptors and reverse the effects of an excessive dose of morphine. A non-competitive antagonist will inactivate a receptor so that an agonist cannot bind to the site.
Faricimab: an investigational agent targeting the Tie-2/angiopoietin pathway and VEGF-A for the treatment of retinal diseases
Published in Expert Opinion on Investigational Drugs, 2021
Massimo Nicolò, Lorenzo Ferro Desideri, Aldo Vagge, Carlo Enrico Traverso
Although anti-VEGF agents are still a first-line treatment option for patients with w-AMD and DME, novel therapeutic strategies are being investigated in order to reduce the treatment burden due to frequent dosing and to improve the clinical outcomes in those patients who had an incomplete clinical response; in addition, real-life studies on VEGF drugs have largely reported inferior results as compared with large, multicenter, pivotal trials leading to their approval [45–47]. In this direction, other investigational pathways are being examined as potential new targets for the treatment of w-AMD and DME; among, the Ang/Tie pathway is attracting interest because its activation has been proven to be involved in the junctional endothelial protein reinforcement and vascular permeability reduction. This molecular effect is mediated by Ang-2 action, which is a Tie 2 receptor competitive antagonist and inhibits its phosphorylation [18].
Targeting the receptor-based interactome of the dopamine D1 receptor: looking for heteromer-selective drugs
Published in Expert Opinion on Drug Discovery, 2019
Verònica Casadó-Anguera, Antoni Cortés, Vicent Casadó, Estefanía Moreno
The bitopic ligand SB269652 (Figure 2(b)) was described as the first allosteric molecule able to distinguish between D2R and D3R monomers and homodimers. This molecule binds in a bitopic mode to one protomer of a dopamine receptor dimer. In this scenario, part of the ligand binds to the orthosteric site and another part to an allosteric site, causing a change in the ability of ligands to bind the orthosteric binding pocket of the other promoter within the homodimer. However, it acts as a competitive antagonist with receptor monomers [139,140]. Thus, when increasing the concentration of a dopamine receptor agonist, more dimers are occupied and more evident is the allosteric effect [140]. As for allosteric ligands, there are no reported bitopic ligands for D1R heteromers.
Do animal models hold value in Autism spectrum disorder (ASD) drug discovery?
Published in Expert Opinion on Drug Discovery, 2019
Kathryn K. Chadman, Stephanie Fernandes, Elizabeth DiLiberto, Robert Feingold
RG7713, is a V1a receptor antagonist that penetrates the brain and was examined as a proof-of-mechanism for the deficits observed in ASD [51]. Adult male subjects with high functioning ASD were given either a single 20 mg dose of RG7713 or a placebo, counterbalanced on two different days [52]. Subjects were assessed in eye tracking, affective speech recognition, reading the mind in the eyes test, olfactory identification, scripted interaction, an abbreviated version of the Aberrant Behavioral Checklist (ABC), Clinical Global Impressions – Improvement scale (CGI-I), and State-Trait Anxiety Inventory (STAI). Results showed an increase in biological motion orienting preference and a decreased ability to detect lust or fear. While not significant, an improvement in abnormal eye gaze patterns, the identification of smells, and the identification of emotions (excluding lust and fear) were observed [52]. A follow up drug, RG7314, has been further studied as it is V1a competitive antagonist with high specificity for V1a over V1b, V2, and oxytocin receptors that are orally available [53]. This drug, also known as balovaptan, has a favorable safety profile and good pharmacokinetic parameters in healthy volunteers [53]. In January 2018, Roche was granted Breakthrough Therapy Designation from the FDA for balovaptan. Currently Roche has two ongoing clinical trials involving balovaptan and its effect on individuals with ASD (NCT03504917 and NCT02901431).