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Receptors 1
Published in James E. Ferrell, Systems Biology of Cell Signaling, 2021
This model predicts that activation maxes out at less than 100%, with the propensity of a ligand to induce the receptor to adopt its activated conformation being determined by K3, which could vary from ligand to ligand. This explains why some ligands act as full agonists—presumably the equilibrium in the K3 step very much favors the activated conformation—while other ligands act as partial agonists (promoting the conformation change more weakly) and still others act as antagonists, binding but not promoting activation at all. The µ-opioid receptor-binding drugs morphine, heroin, and fentanyl are all regarded as full agonists, with maximal binding leading to maximal receptor activation, whereas buprenorphine is a high-affinity partial agonist, with maximal binding causing less-than-maximal activation. For this reason, buprenorphine is sometimes used to treat opioid addiction; it can maintain an addict in a less-than-maximally intoxicated state that can allow the addict to function more normally. The high-affinity µ-opioid receptor-binding drugs naltrexone and naloxone function as antagonists, binding to receptors without promoting receptor activation. For this reason they can save the life of someone overdosing on an opioid agonist, competing with a death-inducing agonist for access to the receptor and thus decreasing receptor activity to levels compatible with life.
A DFT approach to discriminate the antagonist and partial agonist activity of ligands binding to the NMDA receptor
Published in Molecular Physics, 2018
Zeynep Pinar Haslak, Esra Bozkurt, Bercem Dutagaci, Frank De Proft, Viktorya Aviyente, Freija De Vleeschouwer
Agonists keep the LBDs closed, resulting in the opening of the NMDA ion channel, while antagonists act as a wedge between the LBDs, as such preventing the opening of the ion channel and overstimulation of the receptor (Figure 1) [5]. However, it is well known that complete activation or blockage of the receptor has many serious side effects like memory impairment, neurotoxicity or psychotomimetics [6]. On the other hand, a partial agonist can act either as a full agonist or antagonist, i.e. in the presence of excess antagonist, a partial agonist acts like an agonist to reduce the full inhibition effects of the antagonist, depending on the glycine concentration at the receptor. For this reason, employment of partial agonists is becoming more applicable since these compounds are able to regulate the activity at a certain level [7].