Structure-binding—Activity analysis of beta-adrenergic amines—II: Binding to the beta receptor and inhibition of adenylate cyclase

doi:10.1016/0006-2952(78)90101-6

Biochemical Pharmacology

Volume 27, Issue 10, 15 May 1978, Pages 1455-1461

https://doi.org/10.1016/0006-2952(78)90101-6 Get rights and content

Abstract

Over forty adrenergic analogues were tested for their ability to bind to the beta receptor and to inhibit adenylate cyclase in membranes of the turkey erythrocyte. Over a range of five log orders, the affinity of a compound for the beta receptor, as measured by the specific binding of [¹²⁵] hydroxybenzylpindolol, correlated significantly with its ability to inhibit adenylate cyclase. Potency was related to the size of the substituent on the secondary amine, the levo-rotatory configuration, and to the nature of the aromatic group. In contrast to agonists, antagonists permitted a great latitude of aromatic groups. The methoxy bridge linking aromatic and ethanolamine functions was also important but not essential in determining inhibitory activity. The results establish that the structural requirements for activation and inhibition of beta-adrenergic-directed activities are reflected in the interaction at the beta receptor and suggest models to accommodate their effects.

References (9)

E.M. Brown et al.
J. biol. Chem.
(1976)
J. Axelrod
Recent Prog. Horm. Res.
(1975)
A.J. Kaumann et al.
J. biol. Chem.
(1974)
J.P. Bilezikian et al.
Biochem. Pharmac.
(1441)

There are more references available in the full text version of this article.

Cited by (14)

Pronethalol
2007, xPharm: The Comprehensive Pharmacology Reference
β-Adrenoceptors: Three-dimensional structures and binding sites for ligands
2001, Japanese Journal of Pharmacology
Recent progress in analyzing the structures and functions of G-protein coupled receptors (GPCRs) including β-adrenoceptors (β-ARs) has been made by pharmacological, physiological and molecular biological techniques. The three-dimensional (3D) structures, interaction sites with ligands and confor-mational changes of these receptor subtypes due to ligand binding are now better understood by the simulation of these receptors using computer-aided molecular modeling. Based on these techniques, numbers and conformations of amino acid sequences of each subtype (β₁-, β₂- and β₃-ARs) were defined and also interaction sites or modes of interaction between ligands and N-ARs could be analyzed three-dimensionally. In addition, simulation of 3D structures of β-ARs by molecular modeling could clearly determine the limited size, space or pocket for fitting with ligands. These studies will give some clues for the clarification of other GPCRs. Thus, this review summarizes current findings on chemical structures of ligands, amino acid sequences, 3D structures and important amino acids of β-AR subtypes for interacting with ligands obtained from mutagenesis, chimeric studies and molecular modeling techniques.
5-HT<inf>1A</inf> receptor ligands
1997, Pharmacochemistry Library
For 5-HT_1A receptors, many potent and selective ligands belonging to different chemical classes such as aminotetralins, indolylalkylamines, ergolines, aporphines, arylpiperazines, and aryloxyalkylamines are available. The majority of these compounds are agonists or partial agonists. Pure antagonists devoid of any agonistic activity at presynaptic receptors (somatodendritic autoreceptors) or postsynaptic receptors have been identified. The high affinity of the trans phenylcyclopropylamino derivative is destroyed by separation of the cyclopropane ring and the nitrogen atom by one carbon atom. Without loss in affinity, one of the n-propyl groups can be omitted. The second n-propyl is essential for high binding. The unsubstituted analogues, such as 8- MeO-AT, display only a moderate affinity for the 5-HT_1A receptors. This stereo selectivity, however, is reversed if larger di-n-alkyl substituents are introduced. The (S)- enantiomer of the di-n-butyl compound is about two times more potent than the (R)-enantiomer.
The modelling of β<inf>2</inf>-adrenergic receptors
1994, Pharmaceutica Acta Helvetiae
Adrenergic mimetics have many varied pharmacological applications, thus the quest for selective and efficacious ligands. Provided that a reasonable receptor model can be constructed which mimics the key interactions between a ligand and its biological receptor, molecular modelling offers the potential for rational drug design. The β₂-adrenergic receptor models reviewed in this article have increased in sophistication, in line with more information becoming available about the residues involved in ligand binding, as well as the topography of the receptor.
A theoretical study of the influence of noradrenaline ring fluorination on its adrenergic activity
1989, Journal of Molecular Structure: THEOCHEM
An account is given of the differing α- and β-adrenergic activities of the ring fluorinated noradrenaline derivatives. By introducing a formyl group as a model for the adrenergic receptor it is found that the noradrenaline side chain hydroxyl function is oriented away from the phenyl ring. In the case of the ring fluorinated compounds a fluorine-oxygen electrostatic repulsion leads to a preferred phenyl conformation. It is suggested that the α-receptor conformation corresponds to a value of the ring torsion angle, τ, of about 130° whereas 310° is required for the torsion angle when bound to the β-receptor.
Modulation of Cyclic Nucleotide Metabolism and Function by Xenobiotics
1980, Annual Reports in Medicinal Chemistry
This chapter reviews the identification and development of exogenous effectors of cyclic nucleotide metabolism and function since 1977. The chapter describes and investigates Guanylate cyclase and cGMP dependent protein kinase that are functionally similar to their counterparts. Yet, there lies much less understanding of the role of cGMP in either physiology or pathophysiology. D-lysergic acid diethylamide (LSD) and some derivatives can increase activity of a serotonin-responsive adenylate cyclase from the liver fluke. Xanthines continue to generate interest as inhibitors of phosphodiesterase (PDE) and as potential therapeutic agents. HWA inhibited CAMP PDE from bovine bronchi in more potent fashion than aminophylline. PDE inhibitors can also affect cardiovascular function. Antipsychotic drugs from a number of chemical classes displayed high-affinity, calcium-dependent binding to the calcium-dependent activator of cyclic nucleotide PDE. The relationship of this property to clinical efficacy is still unclear. Paraquat, a guanylate cyclase stimulator, can, at higher concentrations, block the cyclic nucleotide increases in rat lung slices caused by histamine or isoproterenol. Sodium nitroprusside that decreases cyclic AMP levels in bovine parathyroid cells stimulated by isoproterenol, dopamine, and choleratoxin elevates the cGMP levels in these cells by itself.

View all citing articles on Scopus

^☆: Supported by Research Grants HL 17813, HL 20859 and a Grant-in-Aid from the New York Heart Association.

^†: Molly Berns Senior Investigator, New York Heart Association; recipient of Research Career Development Award K04 HL 00383.

View full text

Structure-binding—Activity analysis of beta-adrenergic amines—II: Binding to the beta receptor and inhibition of adenylate cyclase☆

Abstract

J. biol. Chem.

Recent Prog. Horm. Res.

J. biol. Chem.

Biochem. Pharmac.