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What Makes a Good Antagonist: Lessons Learned from the Estrogen and Aryl Hydrocarbon Receptors

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Nuclear Receptors

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Abstract

Traditionally, ligands of receptors have been classified as agonists, partial agonists, or antagonists. Study of the estrogen receptor, however, introduced the field of pharmacology to the concept of selective modulators that varied in their ability to either activate or inhibit the receptor. The mechanisms underlying these events were mapped to their unique positions within the ligand-binding cavity of the estrogen receptor and their interactions with key amino acid residues residing within this pocket. Building on these lessons, selective aryl hydrocarbon receptor modulators are currently being developed to finely tune the activities of the aryl hydrocarbon receptor and inhibit disease-modifying processes. These ongoing lessons will challenge modern pharmacologists to develop new tools and approaches for predicting the ultimate pharmacological effects of these emerging therapeutics.

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Notes

  1. 1.

    In this context, a “pure” AHR antagonist is capable of blocking all actions of the AHR with high efficacy, exhibits high AHR-binding affinity, and lacks measureable agonist activity.

Abbreviations

6-MCDF:

6-methoxy-1,3,8-triCDF

AF1/AF2:

Activation function 1/activation function 2

AHR:

Aryl hydrocarbon receptor

AHRE/DRE/XRE:

Aryl hydrocarbon receptor/dioxin/xenobiotic response element

AHRR:

Aryl hydrocarbon receptor repressor

bHLH/PAS:

Basic helix-loop-helix PER, ARNT, SIM

CYP1A1/1B1:

Cytochrome P450 1A1/1B1

DBD:

DNA-binding domain

DC50:

Half-maximal degradation concentration

E2:

17β-estradiol

ER:

Estrogen receptor

ERE:

Estrogen response element

FICZ:

6-formylindolo[3,2-b]carbazole

HSP90:

Heat shock protein of 90 kDa

IC50:

Half-maximal inhibition concentration

ITE:

2-(1′H-indolo-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester

KD:

Equilibrium dissociation constant

LDB:

Ligand-binding domain

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

PROTAC:

Proteolysis-targeting chimera

SAHRD:

Selective aryl hydrocarbon receptor downregulator

SAHRM:

Selective aryl hydrocarbon receptor modulator

SERCA:

Selective estrogen receptor covalent antagonist

SERDs:

Selective estrogen receptor downregulator

SERM:

Selective estrogen receptor modulator

STEAR:

Selective tissue estrogenic activity regulator

TCDD:

2,3,7,8 tetrachlorodibenzo-p-dioxin

XAP HBV:

X-associated protein 2

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  1. Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA

    Hollie I. Swanson

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  1. School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA

    Mostafa Z. Badr

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Swanson, H.I. (2021). What Makes a Good Antagonist: Lessons Learned from the Estrogen and Aryl Hydrocarbon Receptors. In: Badr, M.Z. (eds) Nuclear Receptors. Springer, Cham. https://doi.org/10.1007/978-3-030-78315-0_9

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