Thermodynamic analysis does not allow discrimination of agonists and antagonists at human CCK2S-receptors

Harper, E A; Mitchell, Elizabeth A.; Griffin, Eric P.; Kalindjian, S. Barrett

doi:10.1016/j.ejphar.2007.11.055

Cited by 7 publications

(2 citation statements)

References 51 publications

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“…Instead, the data indicate that agonist binding to the β 2 -AR is similar to the processes described for the cholecystokinin CCK2, dopamine D 2 , histamine H 1 , δ- and μ-opiod, purinergic P2X 1 and serotonin 5-HT 1A receptors, in which agonists bind to the receptors with both enthalpy-driven and entropy-driven mechanisms [4,9]. …”

Section: Discussionmentioning

confidence: 99%

The effect of stereochemistry on the thermodynamic characteristics of the binding of fenoterol stereoisomers to the β2-adrenoceptor

Jóźwiak¹,

Toll²,

Jimenez³

et al. 2010

Biochemical Pharmacology

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The binding thermodynamics of the stereoisomers of fenoterol, (R,R')-, (S,S')- , (R,S')-, and (S,R')-fenoterol, to the β2-adrenergic receptor (β2-AR) have been determined. The experiments utilized membranes obtained from HEK cells stably transfected with cDNA encoding human β2-AR. Competitive displacement studies using [3H]CGP-12177 as the marker ligand were conducted at 4°, 15°, 25°, 30° and 37°C, the binding affinities calculated and the standard enthalpic (ΔH°) and standard entropic (ΔS°) contribution to the standard free energy change (ΔG°) associated with the binding process determined through the construction of van't Hoff plots. The results indicate that the binding of (S,S')- and (S,R')-fenoterol were predominately enthalpy-driven processes while the binding of (R,R')- and (R,S')-fenoterol were entropy-driven. All of the fenoterol stereoisomers are full agonists of the β2-AR, and, therefore, the results of this study are inconsistent with the previously described “thermodynamic agonist-antagonist discrimination”, in which the binding of an agonist to the β-AR is entropy-driven and the binding of an antagonist is enthalpy driven. In addition, the data demonstrate that the chirality of the carbon atom containing the β-hydroxyl group of the fenoterol molecule (the β-OH carbon) is a key factor in the determination of whether the binding process will be enthalpy-driven or entropy-driven. When the configuration at the β-OH carbon is S the binding process is enthalpy-driven while the R configuration produces an entropy-driven process.

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Section: Discussionmentioning

confidence: 99%

The effect of stereochemistry on the thermodynamic characteristics of the binding of fenoterol stereoisomers to the β2-adrenoceptor

Jóźwiak¹,

Toll²,

Jimenez³

et al. 2010

Biochemical Pharmacology

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“…Structures of melfufen (179) and melphalan (180) anticancer drugs. Gastrazole (JB95008), a CCK2 receptor antagonist: 2-Fluoro-ʟ-phenylalanine derivatives are required for the synthesis of gastrazole (JB95008, 181), a potent and highly selective cholecystokinin-2 (CCK2) receptor antagonist, originally developed at the James Black Foundation[104][105][106][107][108][109]. Roberts et al demonstrated its inhibitory activity of gastrin-stimulated growth of pancreatic cancer both in vitro and in vivo studies[110] (Figure 4).…”

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confidence: 99%

Fluorinated phenylalanines: synthesis and pharmaceutical applications

Awad¹,

Ayoup²

2020

Beilstein J. Org. Chem.

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Recent advances in the chemistry of peptides containing fluorinated phenylalanines (Phe) represents a hot topic in drug research over the last few decades. ᴅ- or ʟ-fluorinated phenylalanines have had considerable industrial and pharmaceutical applications and they have been expanded also to play an important role as potential enzyme inhibitors as well as therapeutic agents and topography imaging of tumor ecosystems using PET. Incorporation of fluorinated aromatic amino acids into proteins increases their catabolic stability especially in therapeutic proteins and peptide-based vaccines. This review seeks to summarize the different synthetic approaches in the literature to prepare ᴅ- or ʟ-fluorinated phenylalanines and their pharmaceutical applications with a focus on published synthetic methods that introduce fluorine into the phenyl, the β-carbon or the α-carbon of ᴅ-or ʟ-phenylalanines.

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