Pharmacodynamic model of slow reversible binding and its applications in pharmacokinetic/pharmacodynamic modeling: review and tutorial

Ren, Tianjing; Zhu, Xiang; Jusko, Natalie M.; Krzyzanski, Wojciech; Jusko, William J.

doi:10.1007/s10928-022-09822-y

Cited by 7 publications

(4 citation statements)

References 107 publications

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“…Schild analysis was used to determine surmountable or insurmountable antagonism (Kenakin et al, 2006). Currently, insurmountable antagonism is a hot topic in the field of antihistamines due to the clinical implications of this phenomenon (Copeland, 2021;Ren et al, 2022). Our data show that fexofenadine, mepyramine, acrivastine and cetirizine displayed a different degree of insurmountable antagonism of the hH 1 R responses.…”

Section: Discussionmentioning

confidence: 86%

Pharmacological Characterization of the Zebrafish (Danio Rerio) Histamine H₁Receptor Reveals the Involvement of the Second Extracellular Loop in the Binding of Histamine

McNaught-Flores,

Kooistra,

Chen

et al. 2023

Mol Pharmacol

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The zebrafish (Danio rerio) histamine H 1 receptor gene (zfH 1 R) was cloned in 2007 and reported to be involved in fish locomotion. Yet, no detailed characterization of its pharmacology and signaling properties have so far been reported. In this study, we pharmacologically characterized the zfH 1 R expressed in HEK-293T cells by means of [ 3 H]-mepyramine binding and G protein signaling assays. The zfH 1 R (K D 0.7 nM) displayed similar affinity for the antagonist [ 3 H]-mepyramine as the hH 1 R (K D 1.5 nM), whereas the affinity for histamine is 100-fold higher than for the human H 1 R. The zfH 1 R couples to G q/11 proteins and activates several reporter genes, i.e.NFAT, NFB, CRE, VEGF, COX-2, SRE and AP-1, and zfH 1 R-mediated signaling is prevented by the G q/11 inhibitor YM-254890 and the antagonist mepyramine. Molecular modeling of the zfH 1 R and human H 1 R shows that the binding pockets are identical, implying that variations along the ligand binding pathway could underly the differences in histamine affinity instead. Targeting differentially charged residues in extracellular loop 2 (ECL2) using site-directed mutagenesis revealed that Arg210 45x55 is most likely involved in the binding process of histamine in zfH 1 R. This study aids the understanding of the pharmacological differences between H 1 R orthologs and the role of ECL2 in histamine binding and provides fundamental information for the understanding of the histaminergic system in the zebrafish.

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Section: Discussionmentioning

confidence: 86%

Pharmacological Characterization of the Zebrafish (Danio Rerio) Histamine H₁Receptor Reveals the Involvement of the Second Extracellular Loop in the Binding of Histamine

McNaught-Flores,

Kooistra,

Chen

et al. 2023

Mol Pharmacol

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“…Although slow off-kinetics improve residence time, faster rates may be more suited in certain circumstances . Extensive reviews on slow-binding kinetics and residence time have previously been written concerning drug-design. ,− Since the intention for developing reversible covalent inhibitors is to reduce off-target effects by taking advantage of reversible kinetics, the residence times of the inhibitor with its on- and off-target enzymes should be optimized. , These experiments were performed both in the development of the BTK inhibitor rilzabrutinib and JAK3 RCIs The binding kinetics of the inhibitor match that of reversible covalent inhibitors.…”

Section: General Considerations For Developing Reversible Covalent In...mentioning

confidence: 99%

Reversible Covalent Inhibition─Desired Covalent Adduct Formation by Mass Action

Patel,

Huma,

Duncan

2024

ACS Chem. Biol.

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Covalent inhibition has seen a resurgence in the last several years. Although long-plagued by concerns of off-target effects due to nonspecific reactions leading to covalent adducts, there has been success in developing covalent inhibitors, especially within the field of anticancer therapy. Covalent inhibitors can have an advantage over noncovalent inhibitors since the formation of a covalent adduct may serve as an additional mode of selectivity due to the intrinsic reactivity of the target protein that is absent in many other proteins. Unfortunately, many covalent inhibitors form irreversible adducts with off-target proteins, which can lead to considerable side-effects. By designing the inhibitor to form reversible covalent adducts, one can leverage competing on/off kinetics in complex formation by taking advantage of the law of mass action. Although covalent adducts do form with off-target proteins, the reversible nature of inhibition prevents accumulation of the off-target adduct, thus limiting side-effects. In this perspective, we outline important characteristics of reversible covalent inhibitors, including examples and a guide for inhibitor development.

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“…The half-life of R* will determine effect duration when the agonist's elimination half-life is shorter, resulting in counterclockwise hysteresis of concentration-effect-time curves (the effect outlasts the duration of agonist levels, for example, lisdexamfetamine [76]). While counterclockwise hysteresis (e.g., for morphine [77] and midazolam [78]) is modeled as a delay of equilibrium in a deep 'receptor compartment' [79] or slow receptor dissociation [80], continued ligand-free R* signaling provides a novel parsimonious mechanism, as discussed above with LSD. The extent and role of ligand-free R* signaling still has to be tested for most GPCRs.…”

Section: Involvement In Agonist Effectsmentioning

confidence: 99%

“…If ligand-free R* accounts for a main portion of the ag overall effect, agonists such as etorphine and LSD can reach extreme potencies as small fraction of the receptor population needs to be occupied. Partial agonists s buprenorphine would need to occupy a larger portion of available receptor sites sufficient activated agonist-R* and ligands-free R* is generated for analgesic effec The half-life of R* will determine effect duration when the agonist's elimination h is shorter, resulting in counterclockwise hysteresis of concentration-effect-time (the effect outlasts the duration of agonist levels, for example, lisdexamfetamine While counterclockwise hysteresis (e.g., for morphine [77] and midazolam [ modeled as a delay of equilibrium in a deep 'receptor compartment' [79] or slow re dissociation [80], continued ligand-free R* signaling provides a novel parsim mechanism, as discussed above with LSD. The extent and role of ligand-free R* sig still has to be tested for most GPCRs.…”

Section: Involvement In Agonist Effectsmentioning

confidence: 99%

Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics

Sadee

2023

Molecules

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G-protein-coupled receptors (GPCRs) are ubiquitous sensors and regulators of cellular functions. Each GPCR exists in complex aggregates with multiple resting and active conformations. Designed to detect weak stimuli, GPCRs can also activate spontaneously, resulting in basal ligand-free signaling. Agonists trigger a cascade of events leading to an activated agonist-receptor G-protein complex with high agonist affinity. However, the ensuing signaling process can further remodel the receptor complex to reduce agonist affinity, causing rapid ligand dissociation. The acutely activated ligand-free receptor can continue signaling, as proposed for rhodopsin and μ opioid receptors, resulting in robust receptor activation at low agonist occupancy with enhanced agonist potency. Continued receptor stimulation can further modify the receptor complex, regulating sustained ligand-free signaling—proposed to play a role in opioid dependence. Basal, acutely agonist-triggered, and sustained elevated ligand-free signaling could each have distinct functions, reflecting multi-state conformations of GPCRs. This review addresses basal and stimulus-activated ligand-free signaling, its regulation, genetic factors, and pharmacological implications, focusing on opioid and serotonin receptors, and the growth hormone secretagogue receptor (GHSR). The hypothesis is proposed that ligand-free signaling of 5-HT2A receptors mediate therapeutic effects of psychedelic drugs. Research avenues are suggested to close the gaps in our knowledge of ligand-free GPCR signaling.

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Pharmacodynamic model of slow reversible binding and its applications in pharmacokinetic/pharmacodynamic modeling: review and tutorial

Cited by 7 publications

References 107 publications

Pharmacological Characterization of the Zebrafish (Danio Rerio) Histamine H₁Receptor Reveals the Involvement of the Second Extracellular Loop in the Binding of Histamine

Pharmacological Characterization of the Zebrafish (Danio Rerio) Histamine H₁Receptor Reveals the Involvement of the Second Extracellular Loop in the Binding of Histamine

Reversible Covalent Inhibition─Desired Covalent Adduct Formation by Mass Action

Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics

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Pharmacodynamic model of slow reversible binding and its applications in pharmacokinetic/pharmacodynamic modeling: review and tutorial

Cited by 7 publications

References 107 publications

Pharmacological Characterization of the Zebrafish (Danio Rerio) Histamine H1Receptor Reveals the Involvement of the Second Extracellular Loop in the Binding of Histamine

Pharmacological Characterization of the Zebrafish (Danio Rerio) Histamine H1Receptor Reveals the Involvement of the Second Extracellular Loop in the Binding of Histamine

Reversible Covalent Inhibition─Desired Covalent Adduct Formation by Mass Action

Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics

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Pharmacological Characterization of the Zebrafish (Danio Rerio) Histamine H₁Receptor Reveals the Involvement of the Second Extracellular Loop in the Binding of Histamine

Pharmacological Characterization of the Zebrafish (Danio Rerio) Histamine H₁Receptor Reveals the Involvement of the Second Extracellular Loop in the Binding of Histamine