β-Adrenoceptors

β-Adrenoceptors are widely distributed, found at both central and peripheral sites, and are activated either via norepinephrine released from sympathetic terminals or via epinephrine (E4250, E4375) released from the adrenal medulla. Important physiological consequences of β-adrenoceptor activation include stimulation of cardiac rate and force, relaxation of vascular, urogenital and bronchial smooth muscle, stimulation of renin secretion from the juxta-glomerular apparatus, stimulation of insulin and glucagon secretion from the endocrine pancreas, stimulation of glycogenolysis in liver and skeletal muscle and stimulation of lipolysis in the adipocyte. Prejunctional β-adrenoceptors are present on some central and peripheral nerve terminals, where their activation results in facilitation of stimulation-evoked neurotransmitter release. However, in contrast to the prejunctional α2-adrenoceptors, these prejunctional receptors do not appear to have major physiologic significance. Most β-adrenoceptor mediated actions involve stimulation of adenylyl cyclase via interaction of the agonist-receptor complex with Gs.

Three β-adrenoceptor proteins have been cloned, and the characteristics of these recombinant receptors correspond with those of the three well characterized β-adrenoceptors on native tissues, designated as β1, β2 and β3. Species differences appear to be important for the β3-adrenoceptor, since several selective β3-adrenoceptor agonists can activate rodent, but not human β3-adrenoceptors. There appear to be multiple affinity states of the β1-adrenoceptor, which may explain the distinct pharmacology of a β-adrenoceptor mediating cardiac contractility.

Many useful pharmacological tools are available for β-adrenoceptor characterization. These include agonists capable of selectively activating β1-, β2- or β3-adrenoceptors, as well as antagonists selective for each of the three subtypes. While it was initially thought that cardiac stimulation involved primarily the β1-adrenoceptor, it now appears that all of the receptor subtypes may be involved. Bronchodilation appears to be mediated primarily by the β2-adrenoceptor. The β3-adrenoceptor is responsible for lipolysis in white adipose tissue and thermogenesis in the brown adipose tissue found in rodents. Renin release appears to be mediated by the β1-adrenoceptor.

β2-Adrenoceptor agonists are commonly used as bronchodilators. Selective β3-adrenoceptor agonists are being developed for the treatment of type II diabetes, obesity and overactive bladder. β-Adrenoceptor antagonists, either non subtype-selective or selective for the β1-adrenoceptor, are widely used as antihypertensives, although the mechanism for this action is still not clearly understood. Intra-ocular administration of nonselective β-adrenoceptor antagonists is a common treatment for glaucoma. Carvedilol, a molecule combining nonselective β-adrenoceptor blockade with α1-adrenoceptor blockade, has recently been shown to produce a dramatic reduction in the mortality/morbidity associated with congestive heart failure.

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Currently Accepted Name β1 (A6728) β2 β3
Alternate Name     atypical β
Structural Information 477 aa (human) 413 aa (human) 408 aa (human)
Subtype Selective Agonists Norepinephrine (A7257, A0937)
Xamoterol
Denopamine (D7815)
T-0509
Procaterol (P9180)
Salbutamol (S8260)
Salbutamol hemisulfate (S5013)
Fenoterol (F1016)
BRL 37344 (B169)
CL 316243 (C5976)
SB-226552
Subtype Selective Antagonists CGP20712A (C231)
Betaxolol (B5683)
Atenolol (A7655)
ICI-118,551 (I127)
Butoxamine (B1385)
α-Methylpropranolol
SR 58894
SR 59230A (S8688)
Receptor Selective Agonist Isoproterenol (I5627)
Isoproterenol (I5627)
Isoproterenol (I5627)
Receptor Selective Antagonists Alprenolol
(±)-Propranolol (P0884)
(S)-(–)-Propranolol (P8688)
Pindolol (P0778)
Alprenolol
(±)-Propranolol (P0884)
(S)-(–)-Propranolol (P8688)
Pindolol (P0778)
Bupranolol
Cyanopindolol (C238)
Signal Transduction Mechanisms Gs (increase cAMP) Gs (increase cAMP) Gs (increase cAMP)
Radioligand of Choice [125I]-I-ICYP [125]-I-ICYP [125I]-I-ICYP
Tissue Expression Coronary artery, kidney, heart, CNS Kidney, lung, heart, CNS Adipose Tissue, GI tract vascular endothelium
Physiological Function Cardiac stimulation, coronary vasodilation Smooth muscle relaxation Adipocyte lipolysis, bladder relaxation, thermogenesis
Disease Relevance Hypertension, congestive heart failure Asthma Obesity, diabetes

 

Abbreviations

BRL 37344: (±)-(R*,R*)-(4-[2-([2-(3-Chlorophenyl)-2-hydroxyethyl]amino)propyl]phenoxy)acedic acid
CGP20712A: (±)-2-Hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]phenoxy]propyl]-amino]ethoxy]-benzamide methanesulfonate
CL 316243: (R,R)-5-[2-[[2-(3-Chlorophenyl)-2-hydroxyethyl]-amino]-propyl]1,3-benzodioxole-2,2-dicarboxylate
ICI-118,551: (±)-1-[2,3-(Dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol
ICYP: Iodocyanopindolol
SB-226552: (S)-4-{2-[2-Hydroxy-3-(4-hydroxyphenoxy)propylamino]ethyl}phenoxymethylcyclohexylphosphinic acid
SR 58894: 3-(2-Allylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol hydrochloride
SR 59230: 3-(2-Ethylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol oxalate
T-0509: [(–)-(R)-1-(3,4-Dihydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)-amino]ethanol

 

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References