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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.
Control of blood vessels: extrinsic control by nerves and hormones
Published in Neil Herring, David J. Paterson, Levick's Introduction to Cardiovascular Physiology, 2018
Neil Herring, David J. Paterson
Phaeochromocytoma, a rare tumour of the medullary chromaffin cells, secretes a mixture of catecholamines and causes hypertension. The latter can be treated with a antagonists such as phentolamine (reversible antagonist) or phenoxy- benzamine (irreversible antagonist with a longer half-life).
ENTRIES A–Z
Published in Philip Winn, Dictionary of Biological Psychology, 2003
An antagonist is a DRUG or chemical that binds to a RECEPTOR and blocks it, preventing it operating normally. It may be a COMPETITIVE ANTAGONIST (also known as SURMOUNTABLE ANTAGONIST) (that is, they compete with the natural LIGAND and AGONIST for receptor occupancy) or it may be an unsurmountable antagonist—agonists at whatever concentration cannot overcome these. An IRREVERSIBLE ANTAGONIST is one which remains bound to receptors for very long periods, up to and including forever.
Fezolinetant in the treatment of vasomotor symptoms associated with menopause
Published in Expert Opinion on Investigational Drugs, 2021
Herman Depypere, Christopher Lademacher, Emad Siddiqui, Graeme L Fraser
Elinzanetant is a nonselective NK1R/NK3R pseudo-irreversible antagonist with greater potency at the NK1 receptor (Figure 4) [41]. The compound was initially developed by GlaxoSmithKline for the treatment of addiction disorders [78], prior to being spun-out into KaNDy Therapeutics and most recently acquired by Bayer [79]. KaNDy Therapeutics demonstrated that elinzanetant is effective in the treatment of VMS in a phase II trial [80]. The potent action of elinzanetant on NK1 receptors is posited to bring some benefit with regard to peripheral flushing and sleep in VMS [80], whereas the alternate effects of NK1 antagonists on centrally mediated emesis and addiction circuits [26,27], gastrointestinal pharmacology [28], and the hypothalamic-pituitary-adrenal axis [81] is of unknown consequence in menopausal women. Additional clinical testing will further characterize the NK1R/NK3R pharmacology of elinzanetant.
Approaches for designing and discovering purinergic drugs for gastrointestinal diseases
Published in Expert Opinion on Drug Discovery, 2020
Diego Dal Ben, Luca Antonioli, Catia Lambertucci, Andrea Spinaci, Matteo Fornai, Vanessa D’Antongiovanni, Carolina Pellegrini, Corrado Blandizzi, Rosaria Volpini
Agonists of the P2XRs were developed based on the structure of the endogenous ligand ATP, modified at the triphosphate chain, the purine moiety, or the ribose ring [18,49,50]. The low chemical stability of ATP was at the basis of the development of αβ-meATP and ATPγS (Figure 2, ATPγS active also at P2YRs), or βγ-meATP (Figure 2), compounds endowed with agonist activity at the P2XRs and less susceptible to degradation by ectonucleotidases. Modifications of the purine moiety or the ribose ring led to compounds like 2-meSATP (Figure 2) and BzATP [18], compounds active also at the P2YRs. Inhibitors of the P2XRs were obtained as ATP competitive antagonists or as noncompetitive inhibitors. Some of these derivatives were developed again as ATP derivatives, modified at the sugar ring to obtain, i.e. oxidized-ATP (oATP, irreversible antagonist of the P2X7 receptor) or the potent P2X1/P2X3 inhibitor TNP-ATP (Figure 2) [18,49]. An ATP-competitive inhibitor of the P2X3 receptor was also obtained even if not as ATP derivative, A-317491 (Figure 2) [49]. Further classes of P2XRs inhibitors were obtained based on various structural classes like suramin-like analogues [18] or anthraquinones (i.e. the P2X2 selective antagonists PSB-10211 and PSB-1011) [51]. Some derivatives behave as inhibitors of both P2XRs and P2YRs, like suramin or PPADS (Figure 2). A significant number of P2X7 inhibitors was developed and reported due to the great interest in this P2XR subtype as possible therapeutic target [52,53]. Among these compounds, AZD9056 (Figure 2) was clinically tested for the treatment of moderately to severely active Crohn’s Disease, showing to improve symptoms in patients [54]. Compounds able to inhibit the P2X4R at sub-micromolar (5-BDBD [55], NP-1815-PX [56], and BX430 [57]) or micromolar (PSB-12062 [58]) concentrations were also reported.