Biochemical and pharmacological characterization of high-affinity trimetoquinol analogs on guinea pig and human beta adrenergic receptor subtypes: evidence for partial agonism.

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Fraundorfer PF, Fertel RH, Miller DD, Feller DR

Biochemical and pharmacological characterization of high-affinity trimetoquinol analogs on guinea pig and human beta adrenergic receptor subtypes: evidence for partial agonism.

J Pharmacol Exp Ther. 1994 Aug;270(2):665-74.

PubMed ID

7915318 [ View in PubMed

]

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-tetrahydroisoqui nol ine; 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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Pindolol	Beta-1 adrenergic receptor	Ki (nM)	1.94	N/A	N/A	Details
Propranolol	Beta-1 adrenergic receptor	Ki (nM)	2.69	N/A	N/A	Details