Biochemical and pharmacological characterization of high-affinity trimetoquinol analogs on guinea pig and human beta adrenergic receptor subtypes

Evidence for partial agonism

P. F. Fraundorfer, R. H. Fertel, Duane Miller, D. R. Feller

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Radioligand binding assays were used to characterize the interaction of a series of trimetoquinol {1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline; TMQ} analogs with beta adrenergic receptors (beta-AR). The results indicated that TMQ analogs bound with similar affinities to guinea pig (heart, lung and skeletal muscle) and human (beta- AR in Escherichia coli) beta-1- and beta-2-AR subtypes. However, the isomers of TMQ and 8-fluoro-TMQ bound stereoselectively to beta-AR with the S- isomers having affinities at least 112- and 8-fold greater, respectively, than their corresponding R-isomers. In general, a direct relationship existed between TMQ analog binding to guinea pig beta-AR and functional activity on guinea pig right atria (beta-1) and trachea (beta-2). For selected halogenated TMQ analogs (3',5'-diiodo-TMQ, 3'-iodo-TMQ, 5,8-difluoro-TMQ and 5-iodo-TMQ) which had higher beta-AR affinities than TMQ, but were less potent beta-AR agonists than TMQ, this relationship was not seen. To explain this, the function of the TMQ analogs was analyzed at the level of the beta- AR-associated effector mechanism (i.e., G-protein and adenylyl cyclase). In Chinese hamster ovary cells expressing human beta-2-AR, TMQ and halogenated analogs bound to the receptor with high affinity (nanomolar range); however, they failed to effectively couple with beta-AR-associated G-protein and only partially activated receptor-associated adenylyl cyclase. Receptor occupancies of 0.14, 2 and 23% were required for (-)-isoproterenol, S-(-)- TMQ and 3'5'-diiodo-TMQ to produce equivalent cyclic AMP accumulations in human beta-2-AR Chinese hamster ovary cells. Thus, TMQ and halogenated TMQ derivatives bind stereoselectively to beta-AR with high affinity, and may be classified as partial beta-AR agonists.

Original languageEnglish (US)
Pages (from-to)665-674
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume270
Issue number2
StatePublished - 1994
Externally publishedYes

Fingerprint

Tretoquinol
Receptors, Adrenergic, beta
Guinea Pigs
Pharmacology
Adrenergic beta-Agonists
Cricetulus
GTP-Binding Proteins
Adenylyl Cyclases
Ovary
Radioligand Assay
Trachea
Heart Atria
Isoproterenol
Cyclic AMP
Myocardium
Skeletal Muscle
Escherichia coli
Lung

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

@article{db04179955634992bb52b841ebc2ae83,
title = "Biochemical and pharmacological characterization of high-affinity trimetoquinol analogs on guinea pig and human beta adrenergic receptor subtypes: Evidence for partial agonism",
abstract = "Radioligand binding assays were used to characterize the interaction of a series of trimetoquinol {1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline; TMQ} analogs with beta adrenergic receptors (beta-AR). The results indicated that TMQ analogs bound with similar affinities to guinea pig (heart, lung and skeletal muscle) and human (beta- AR in Escherichia coli) beta-1- and beta-2-AR subtypes. However, the isomers of TMQ and 8-fluoro-TMQ bound stereoselectively to beta-AR with the S- isomers having affinities at least 112- and 8-fold greater, respectively, than their corresponding R-isomers. In general, a direct relationship existed between TMQ analog binding to guinea pig beta-AR and functional activity on guinea pig right atria (beta-1) and trachea (beta-2). For selected halogenated TMQ analogs (3',5'-diiodo-TMQ, 3'-iodo-TMQ, 5,8-difluoro-TMQ and 5-iodo-TMQ) which had higher beta-AR affinities than TMQ, but were less potent beta-AR agonists than TMQ, this relationship was not seen. To explain this, the function of the TMQ analogs was analyzed at the level of the beta- AR-associated effector mechanism (i.e., G-protein and adenylyl cyclase). In Chinese hamster ovary cells expressing human beta-2-AR, TMQ and halogenated analogs bound to the receptor with high affinity (nanomolar range); however, they failed to effectively couple with beta-AR-associated G-protein and only partially activated receptor-associated adenylyl cyclase. Receptor occupancies of 0.14, 2 and 23{\%} were required for (-)-isoproterenol, S-(-)- TMQ and 3'5'-diiodo-TMQ to produce equivalent cyclic AMP accumulations in human beta-2-AR Chinese hamster ovary cells. Thus, TMQ and halogenated TMQ derivatives bind stereoselectively to beta-AR with high affinity, and may be classified as partial beta-AR agonists.",
author = "Fraundorfer, {P. F.} and Fertel, {R. H.} and Duane Miller and Feller, {D. R.}",
year = "1994",
language = "English (US)",
volume = "270",
pages = "665--674",
journal = "Journal of Pharmacology and Experimental Therapeutics",
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TY - JOUR

T1 - Biochemical and pharmacological characterization of high-affinity trimetoquinol analogs on guinea pig and human beta adrenergic receptor subtypes

T2 - Evidence for partial agonism

AU - Fraundorfer, P. F.

AU - Fertel, R. H.

AU - Miller, Duane

AU - Feller, D. R.

PY - 1994

Y1 - 1994

N2 - Radioligand binding assays were used to characterize the interaction of a series of trimetoquinol {1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline; TMQ} analogs with beta adrenergic receptors (beta-AR). The results indicated that TMQ analogs bound with similar affinities to guinea pig (heart, lung and skeletal muscle) and human (beta- AR in Escherichia coli) beta-1- and beta-2-AR subtypes. However, the isomers of TMQ and 8-fluoro-TMQ bound stereoselectively to beta-AR with the S- isomers having affinities at least 112- and 8-fold greater, respectively, than their corresponding R-isomers. In general, a direct relationship existed between TMQ analog binding to guinea pig beta-AR and functional activity on guinea pig right atria (beta-1) and trachea (beta-2). For selected halogenated TMQ analogs (3',5'-diiodo-TMQ, 3'-iodo-TMQ, 5,8-difluoro-TMQ and 5-iodo-TMQ) which had higher beta-AR affinities than TMQ, but were less potent beta-AR agonists than TMQ, this relationship was not seen. To explain this, the function of the TMQ analogs was analyzed at the level of the beta- AR-associated effector mechanism (i.e., G-protein and adenylyl cyclase). In Chinese hamster ovary cells expressing human beta-2-AR, TMQ and halogenated analogs bound to the receptor with high affinity (nanomolar range); however, they failed to effectively couple with beta-AR-associated G-protein and only partially activated receptor-associated adenylyl cyclase. Receptor occupancies of 0.14, 2 and 23% were required for (-)-isoproterenol, S-(-)- TMQ and 3'5'-diiodo-TMQ to produce equivalent cyclic AMP accumulations in human beta-2-AR Chinese hamster ovary cells. Thus, TMQ and halogenated TMQ derivatives bind stereoselectively to beta-AR with high affinity, and may be classified as partial beta-AR agonists.

AB - Radioligand binding assays were used to characterize the interaction of a series of trimetoquinol {1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline; TMQ} analogs with beta adrenergic receptors (beta-AR). The results indicated that TMQ analogs bound with similar affinities to guinea pig (heart, lung and skeletal muscle) and human (beta- AR in Escherichia coli) beta-1- and beta-2-AR subtypes. However, the isomers of TMQ and 8-fluoro-TMQ bound stereoselectively to beta-AR with the S- isomers having affinities at least 112- and 8-fold greater, respectively, than their corresponding R-isomers. In general, a direct relationship existed between TMQ analog binding to guinea pig beta-AR and functional activity on guinea pig right atria (beta-1) and trachea (beta-2). For selected halogenated TMQ analogs (3',5'-diiodo-TMQ, 3'-iodo-TMQ, 5,8-difluoro-TMQ and 5-iodo-TMQ) which had higher beta-AR affinities than TMQ, but were less potent beta-AR agonists than TMQ, this relationship was not seen. To explain this, the function of the TMQ analogs was analyzed at the level of the beta- AR-associated effector mechanism (i.e., G-protein and adenylyl cyclase). In Chinese hamster ovary cells expressing human beta-2-AR, TMQ and halogenated analogs bound to the receptor with high affinity (nanomolar range); however, they failed to effectively couple with beta-AR-associated G-protein and only partially activated receptor-associated adenylyl cyclase. Receptor occupancies of 0.14, 2 and 23% were required for (-)-isoproterenol, S-(-)- TMQ and 3'5'-diiodo-TMQ to produce equivalent cyclic AMP accumulations in human beta-2-AR Chinese hamster ovary cells. Thus, TMQ and halogenated TMQ derivatives bind stereoselectively to beta-AR with high affinity, and may be classified as partial beta-AR agonists.

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