Dose–Response Curves
Kate McCombe, Lara Wijayasiri, Paul Hatton, David Bogod in The Primary FRCA Structured Oral Examination Study Guide 2, 2017
Potency describes the dose of drug required to produce a response of a given magnitude. A drug with a high potency requires a smaller dose than one of low potency to produce the same effect. Usually, the more lipid soluble a drug, the greater is its potency, e.g. fentanyl (1 µg/kg) is more potent than alfentanil (10 µg/kg).ED50 is used to define potency and compare drugs.Affinity describes how avidly a drug binds to its receptor. This is irrespective of whether the drug–receptor interaction produces a response or not.Intrinsic activity describes the extent to which the drug activates or stimulates a receptor once bound.Efficacy describes the ability of a drug to produce the maximal response or effect once it is bound to its receptor.
Clinical pharmacology: opioids
Pamela E Macintyre, Suellen M Walker, David J Rowbotham in Clinical Pain Management, 2008
Efficacy (or intrinsic activity) is a concept which describes the magnitude of the maximal response of a tissue arising from a drug–receptor interaction.3 Potency is an expression of the activity of the drug, in terms of the amount needed to produce a defined effect.3 The relationship between these terms is best illustrated by considering morphine, fentanyl, and buprenorphine. Morphine has the same efficacy as fentanyl (both can cause respiratory arrest). Unfortunately, the term potency is often used in general conversation synonymously with the term efficacy, i.e. “morphine is just as potent as fentanyl.” In pharmacological terms, this is incorrect because fentanyl is more potent than morphine as the ED50 (the dose that is effective in 50 percent of patients for any defined effect) is less than that of morphine. Under normal circumstances, buprenorphine does not cause respiratory depression. Therefore, it is less efficacious (in terms of effect on the respiratory system) than morphine. It is also less efficacious as an analgesic (see below under Buprenorphine). However, because the dose of buprenorphine is far smaller than morphine (e.g. 0.3–0.6mg intramuscularly (i.m.)), it has a smaller ED50. Therefore, buprenorphine is more potent than morphine.
Third Histamine Receptor: From Discovery to Clinics, Long-Lasting Love Story at INSERM and Bioprojet
Divya Vohora in The Third Histamine Receptor, 2008
More importantly, we found that the H3 receptor was endowed with large constitutive activity. Finding that, using artificial cell systems in which the receptor is overexpressed, is certainly trivial, since this has been reported with many members of the superfamily and might be regarded as a kind of artifact of little physiological relevance. But, quite interestingly, we discovered that only this receptor, among a number of others, displayed constitutive activity when tested in native form, in cerebral membranes. Furthermore, using proxyfan, a neutral antagonist (i.e., a compound able to block the effect of agonists but not to reverse the receptor constitutive activity), which we had identified in our chemical library, we showed that only reversal of the constitutive activity (by inverse agonists) can enhance transmitter release from histaminergic terminals [18]. This observation is of high potential importance for therapeutic applications inasmuch as it suggests that inverse agonists, in contrast with neutral antagonists, may have different intrinsic activities and, thereby exert different effects (or, at least, different maximal effects) in vivo. In agreement with these theoretical views, we have observed that diverse inverse agonists display different degrees of intrinsic activity [19].
The positive allosteric modulation of GABAA receptors mRNA in immature hippocampal rat neurons by midazolam affects receptor expression and induces apoptosis
Published in International Journal of Neuroscience, 2019
Barbara Sinner, Julia Steiner, Manuela Malsy, Bernhard M. Graf, Anika Bundscherer
Glutamate and GABA are both essential neurotransmitters during brain development. Initially, both neurotransmitters act in a paracrine fashion until synapses are developed. The contribution of GABA and NMDA receptors to the first synaptic-driven synchronous activities is essential [15]. In models of rat occipital cortex long-term blockade of glutamate receptors in immature neurons with the NMDA receptor antagonist MK 801 lead to an increase and dysbalance in glutamate receptor expression [16–18]. This change in receptor expression resulted in the restoration of intrinsic activity. Recently, our group [6] showed that long-term application of the anesthetic ketamine, a NMDA receptor antagonist, induced a significant increase in NR 1 receptor expression in immature neurons which was associated with increased neuronal excitability. The rise in glutamate receptors was associated with enhanced apoptosis. In addition, our group demonstrated that Ca2+-oscillations in hippocampal are suppressed by benzodiazepines like glutamate and this was associated with significant morphological alterations [10,19].
Preclinical discovery and development of oliceridine (Olinvyk®) for the treatment of post-operative pain
Published in Expert Opinion on Drug Discovery, 2022
Ammar A.H. Azzam, David G. Lambert
The issue of intrinsic activity has been addressed in a systematic analysis of a wide range of opioids (encompassing the main putative biased MOP ligands; oliceridine, PZM-21, and SR-17018) by Gillis and colleagues in 2020 [29]. In this pivotal piece of work, they utilized a comprehensive range of in vitro signaling assays through to in vivo behavioral testing. In assays of G-protein signaling (Nb33 nanobody and mini Gi recruitment, activation of Gαi2, inhibition of cAMP and GIRK activation) against DAMGO; oliceridine, PZM21, and SR-17018 all displayed low intrinsic activity. Moreover, low intrinsic activity for these ‘putative biased’ agonists against DAMGO was also reported in assays for receptor regulation (GRK2 and β-Arrestin-2 recruitment and MOP trafficking in Rab5 positive endosomes). Receptor phosphorylation barcode also correlated with intrinsic efficacy [29].
Aripiprazole for the treatment of schizophrenia: Recommendations of a panel of Spanish experts on its use in clinical practice
Published in International Journal of Psychiatry in Clinical Practice, 2023
David Fraguas, David Almenta Gallego, Sergio Arques-Egea, Marcos Gómez-Revuelta, Carlos Gómez Sánchez-Lafuente, Daniel Hernández Huerta, Daniel Núñez Arias, Beatriz Oda Plasencia-García, Carlos Parro Torres, Samuel Leopoldo Romero-Guillena, Elena Ros Cucurul, Cecilio Alamo
Aripiprazole is considered a second-generation antipsychotic, although its pharmacodynamic characteristics have led some authors to consider it a third-generation antipsychotic (Freudenreich, 2020; Rivas-Vazquez, 2003). Specifically, aripiprazole is a partial agonist (less intrinsic activity than the physiological ligand) with a high affinity for dopamine D2 receptor (R-D2) and R-D3 and the serotonin receptor R-5-HT1A, combined with an antagonistic activity on the R-5-HT2A receptor (Mamo et al., 2007). In addition, this antipsychotic also has a moderate affinity for receptors R-5-HT7 (Sarkisyan et al., 2010) and R-5-HT2C, acting over them as a partial agonist (Álamo & Arnáez Zaragoza, 2018).