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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.
Finding a Target
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Drugs operate in the cell by interrupting a biochemical process such that there is a change in the activity of the cell, causing a noticeable effect. They may enter the cell via transport proteins in the cell membrane, or if they are suitably hydrophobic pass straight through the phospholipid bilayer. On the other hand, the drug might target receptors on the outer surface of the cell. How a drug reaches the target is an important factor of consideration for the medicinal chemist. The drug molecules must reach the site of action in sufficient concentration to be effective and this may affect the route of administration of the compound. Compounds that are not assimilated well when taken orally may have to be injected. Chemists can alter the properties of the molecule to make it more orally bioavailable, but this must not impede the interaction of the drug with the target. Drugs can be designed to target specific enzymes, cell receptors, and even nucleic acids. A drug molecule’s ability to interact with the target is paramount to determining its efficacy.
Regulation of Airway Smooth Muscle Proliferation by β2-Adrenoceptor Agonists
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
Alastair G. Stewart, Paul R. Tomlinson, Leslie Schachte
Short-term exposure to β2-adrenoceptor agonists leads to a rapid desensitisation involving receptor sequestration. Longer-term exposure causes a decrease in receptor expression, referred to as downregulation, resulting from a decrease in the total amount of receptor protein.
Neural Plasticity in the Ventral Tegmental Area, Aversive Motivation during Drug Withdrawal and Hallucinogenic Therapy
Published in Journal of Psychoactive Drugs, 2023
Hector Vargas-Perez, Taryn Elizabeth Grieder, Derek van der Kooy
It is important to note that the expression of 5-HT2A receptors is increased in several pathologies, such as migraine (Srikiatkhachorn, Govitrapong, and Limthavon 1994), but in particular a dramatic increase in these receptors has been observed in the brains of patients with depressive disorders and in individuals who have committed suicide (Pandey et al. 2002). Moreover, the elevated expression of 5-HT2A receptors in the VTA increases the vulnerability of rats to the behavioral effects induced by cocaine, suggesting that 5-HT2A receptor in the VTA plays a role in regulation of responsiveness to stimulant substances (Herin et al. 2013). As occurs with other members of families of G-protein coupled receptors signaling through the 5-HT2A receptor produces a phenomenon of negative regulation of the same receptor (Buckholtz, Zhou, and Freedman 1988). Thus, each time these receptors are activated, there is a decrease in their expression, and the probability of their cell surface expression decreases (Buckholtz, Zhou, and Freedman 1988). In this way, the use of hallucinogenic substances decrease the production of 5-HT2A receptors (Raval et al. 2021), thus reversing the increase associated with pathological states, including depression and substance use.
Flow cytometry and receptor occupancy in immune-oncology
Published in Expert Opinion on Biological Therapy, 2022
Alessandra Audia, Gregory Bannish, Rachel Bunting, Chelsea Riveley
The biology of the target receptor and its role in delivering the biotherapeutic message to the cells in order to modify a mechanism otherwise altered, is of fundamental importance for design of a ROA. In association to these methods, modulation of ROA can be designed to assess modification in the biologic turnover of the receptor upon binding to the biotherapeutic. These modifications may involve up-regulation, down-regulation, internalization of the target receptor or even release of membrane-bound receptors. Modulation of ROA can be also used to assess drug interference during combo treatment (labeled biotherapeutic in combination with therapeutic B) that can be observed through change in fluorescence of the labeled biotherapeutic (Figure 2). Receptor modulation assessment can be performed by monitoring changes in total receptor relative to drug treatment dosage and time.
The enigmatic nature of the triggering receptor expressed in myeloid cells -1 (TLT- 1)
Published in Platelets, 2021
Siobhan Branfield, A. Valance Washington
Key to understanding the function of any receptor is the identification of its ligand. In our early studies we proposed fibrinogen as a ligand of TLT-1 and suggested that during platelet aggregation, TLT-1 cross-links extracellular fibrinogen, stabilizing higher-order platelet aggregates [18]. In this study, lysates generated from purified human platelets were applied to AminoLink columns preloaded with either sTLT-1 or sTREM-1. This approach revealed specific binding of 3 proteins with molecular masses between 50 and 80 kDa on a Coomassie stained gel. Mass spectroscopy identified these proteins as the α, β, and γ chains of fibrinogen. To confirm these findings, fibrinogen was also eluted from His-tagged TLT-1 but not TREM-1 bound to nickel columns and resolved by PAGE in either native or reduced conditions. Consistent with disulfide-linked multimers of fibrinogen, TLT-1 column specifically bound a high molecular weight complex that when reduced resolved into the same 3 bands detected with AminoLink columns. Immunoblotting with anti-fibrinogen confirmed the identity of these TLT-1–interacting proteins as fibrinogen. This was further supported by ELISA, confirming fibrinogen as a TLT-1 ligand. While the identification of fibrinogen as a ligand was expected to bring answers, it only generated larger questions.