China
Africa
Explore chapters and articles related to this topic
Basic psychopharmacology
Published in Jonathan P Rogers, Cheryl CY Leung, Timothy RJ Nicholson, Pocket Prescriber Psychiatry, 2019
Jonathan P Rogers, Cheryl CY Leung, Timothy RJ Nicholson
The target for a drug is a neurotransmitter receptor. Postsynaptic receptors mediate a response in the postsynaptic neuron. Presynaptic receptors are usually autoreceptors that exert a negative feedback effect on release of the neurotransmitter. There are several possible actions on a receptor: An agonist binds the receptor in the same location, and stimulates the receptor to the same degree, as the neurotransmitter; e.g. methadone is an agonist at the μ opioid receptor.An antagonist binds the receptor in the same location as the neurotransmitter, but it does not stimulate it, blocking the neurotransmitter from acting; e.g. most antipsychotics are antagonists at the dopamine D2 receptor.A partial agonist binds the receptor in the same location as the neurotransmitter, but it stimulates it to a lower degree than the neurotransmitter. If levels of the neurotransmitter are low, a partial agonist will increase the postsynaptic response by providing some receptor stimulation. If levels of the neurotransmitter are high, a partial agonist will reduce the postsynaptic response by blocking the neurotransmitter from binding the receptor. For example, aripiprazole is a partial agonist at the dopamine D2 receptor, and buspirone is a partial agonist at the serotonin 5-HT1A receptor.A positive allosteric modulator binds to a different site on the receptor from the one that the neurotransmitter binds to; it increases the response of the receptor to the neurotransmitter. For example, benzodiazepines bind to the GABAA receptor at a site different from the GABA binding site and facilitate the opening of the chloride channel by GABA.A negative allosteric modulator binds to a different site on the receptor from the one that the neurotransmitter binds to; it reduces the response of the receptor to the neurotransmitter. For example, ketamine binds to the ion channel of the glutamatergic NMDA receptor, reducing its activity.
Achieving and Sustaining Precision Effects
Published in Betty Wedman-St Louis, Cannabis as Medicine, 2019
Adjacent on the sides of the center column is the type of connection, either THC or CBD, produced at each of them. Generally speaking, these two cannabinoids can behave or act as an agonist, antagonist, inverse agonist, allosteric modulator, or a neurotransmitter modulator. Agonist (white circle): A compound such as THC, CBD, or any drug that binds to a specific receptor such as CB1 or CB2 and produces a specific biological effect. You may want to think of an agonist as a light switch that turns an option on.Antagonist (gray circle): A compound that binds to the same receptor site as an agonist does but instead blocks or reduces the normal response. Continuing with the switch analogy, an antagonist either dims the light or turns it off.Allosteric modulator: Allosteric binding sites are indirect binding sites that can influence an agonist and antagonist. In contrast, orthosteric binding sites are direct or primary binding sites of a receptor to a compound.Selective (allosteric) antagonist of CB1/CB2receptor agonists: When you look at the fields on the right side next to CB1 and CB2, you will notice that CBD is indicated to be both an agonist (white circle) and an antagonist (gray circle). CBD is a very weak agonist at CB1 and CB2 but at the same time functions as a tissue-specific allosteric (indirect) modulator of CB1 and CB2 agonists. As such, and practically speaking, CBD can act differently in different types of tissues, resulting in its capacity to reduce the effects of CB1 and CB2 agonists such as THC. In other words, this is the reason why CBD appears to tame some of the psychoactive effects of THC.Neurotransmitter modulation via the endocannabinoid system inhibits or enhances, either in part or significantly, the release of over 20 diverse communication molecules such as neurotransmitters, hormones, pro- and anti-inflammatory cytokines, endogenous opioids such as dopamine, GABA, glutamate, oxytocin, serotonin, cortisol, epinephrine, and acetylcholine, for example.
Unmasking allosteric-binding sites: novel targets for GPCR drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Verònica Casadó-Anguera, Vicent Casadó
- An allosteric modulator is a ligand that can modify the action of the endogenous activator, an orthosteric agonist or of an antagonist when is bound to the allosteric site on the receptor. Allosteric modulators can be positive (PAM), negative (NAM) or silent (SAM). A PAM increases the affinity and/or efficacy of an orthosteric agonist, activator, or antagonist. In contrast, a NAM decreases the affinity and/or efficacy of an orthosteric agonist, activator, or antagonist. Instead, an orthosteric agonist is ‘a ligand that binds to the orthosteric site of a receptor and modifies the receptor state, generating a biologic response. Conventional orthosteric agonists increase receptor activity, whereas orthosteric inverse agonists reduce it.’ A SAM is a ligand that binds to the allosteric site of a receptor but does not alter the affinity and/or efficacy of an orthosteric agonist, activator, or antagonist. Thus, a SAM (or ‘neutral allosteric ligand,’ NAL), via a steric interaction, can ‘prevent the binding of other allosteric ligands to the same allosteric site,’ and can act as a PAM or NAM of other ligands, including allosteric ligands binding to a different allosteric site on the receptor or different orthosteric ligands [5].
Hidden allosteric sites and De-Novo drug design
Published in Expert Opinion on Drug Discovery, 2022
Ashfaq Ur Rehman, Shaoyong Lu, Abdul Aziz Khan, Beenish Khurshid, Salman Rasheed, Abdul Wadood, Jian Zhang
A diversity of protein conformations can be sampled by large-scale unbiased molecular dynamic (MD) simulations of proteins. Several low-populated conformations sampled by MD simulations are unable to be identified by experimental methods. Such minor conformations have hidden allosteric sites that can be targeted in allosteric modulator design. G-protein-coupled receptors (GPCRs) are the largest class of drug candidates, with one-quarter of most GPCR marked drugs. Using BQZ12; a PAM (positive allosteric modulator), which is highly selective to M1 instead of M2-M5 mAChRs, in complex with the most subtype-selective GPCR modulators [90,114]. The mAChRs is an effective strategy to improve therapies for a wide range of psychological, neurological, and peripheral diseases with small molecules [90,115–118].
GLP-1R agonists for the treatment of obesity: a patent review (2015-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Chunxia Liu, Yuxing Zou, Hai Qian
In GPCRs, the binding site of a natural ligand is called an orthosteric site, and a ligand that binds competitively with the natural ligand at this site is an orthosteric ligand. The binding pocket of the orthomorphic ligand is relatively conservative, usually located inside the 7th transmembrane helix near the extracellular side, and the binding site that is different in space and shape from the orthomorphic site is called an allosteric site. According to the different functions of allosteric modulators bound to allosteric sites, allosteric modulators are divided into positive allosteric modulators (PAM) and negative allosteric modulator of agonist effect (NAM). The diversity of allosteric site sequences and structures in a single GPCR subfamily provides a new idea for the development of selective GPCR modulators. Allosteric modulators target non-conserved allosteric sites and interact with normal ligands. They have unique advantages, including higher specificity and lower toxicity and represent an innovative strategy for drug discovery.