ICI 118,551 hydrochloride

ICI 118551 is a selective beta 2 adrenoceptor antagonist.

Modulation of neuroinflammation and pathology in the 5XFAD mouse model of Alzheimer's disease using a biased and selective beta-1 adrenergic receptor partial agonist.[Pubmed:28089846]

Neuropharmacology. 2017 Apr;116:371-386.

Degeneration of noradrenergic neurons occurs at an early stage of Alzheimer's Disease (AD). The noradrenergic system regulates arousal and learning and memory, and has been implicated in regulating neuroinflammation. Loss of noradrenergic tone may underlie AD progression at many levels. We have previously shown that acute administration of a partial agonist of the beta-1 adrenergic receptor (ADRB1), xamoterol, restores behavioral deficits in a mouse model of AD. The current studies examined the effects of chronic low dose xamoterol on neuroinflammation, pathology, and behavior in the pathologically aggressive 5XFAD transgenic mouse model of AD. In vitro experiments in cells expressing human beta adrenergic receptors demonstrate that xamoterol is highly selective for ADRB1 and functionally biased for the cAMP over the beta-arrestin pathway. Data demonstrate ADRB1-mediated attenuation of TNF-alpha production with xamoterol in primary rat microglia culture following LPS challenge. Finally, two independent cohorts of 5XFAD and control mice were administered xamoterol from approximately 4.0-6.5 or 7.0-9.5 months, were tested in an array of behavioral tasks, and brains were examined for evidence of neuroinflammation, and amyloid beta and tau pathology. Xamoterol reduced mRNA expression of neuroinflammatory markers (Iba1, CD74, CD14 and TGFbeta) and immunohistochemical evidence for microgliosis and astrogliosis. Xamoterol reduced amyloid beta and tau pathology as measured by regional immunohistochemistry. Behavioral deficits were not observed for 5XFAD mice. In conclusion, chronic administration of a selective, functionally biased, partial agonist of ADRB1 is effective in reducing neuroinflammation and amyloid beta and tau pathology in the 5XFAD model of AD.

Heat Shock-Related Protein 20 Peptide Decreases Human Airway Constriction Downstream of beta2-Adrenergic Receptor.[Pubmed:26909644]

Am J Respir Cell Mol Biol. 2016 Aug;55(2):225-33.

Severe bronchospasm refractory to beta-agonists is a challenging aspect of asthma therapy, and novel therapeutics are needed. beta-agonist-induced airway smooth muscle (ASM) relaxation is associated with increases in the phosphorylation of the small heat shock-related protein (HSP) 20. We hypothesized that a transducible phosphopeptide mimetic of HSP20 (P20 peptide) causes relaxation of human ASM (HASM) by interacting with target(s) downstream of the beta2-adrenergic receptor (beta2AR) pathway. The effect of the P20 peptide on ASM contractility was determined in human and porcine ASM using a muscle bath. The effect of the P20 peptide on filamentous actin dynamics and migration was examined in intact porcine ASM and cultured primary HASM cells. The efficacy of the P20 peptide in vivo on airway hyperresponsiveness (AHR) was determined in an ovalbumin (OVA) sensitization and challenge murine model of allergic airway inflammation. P20 peptide caused dose-dependent relaxation of carbachol-precontracted ASM and blocked carbachol-induced contraction. The beta2AR inhibitor, (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-buta nol hydrochloride (ICI 118,551), abrogated isoproterenol but not P20 peptide-mediated relaxation. The P20 peptide decreased filamentous actin levels in intact ASM, disrupted stress fibers, and inhibited platelet-derived growth factor-induced migration of HASM cells. The P20 peptide treatment reduced methacholine-induced AHR in OVA mice without affecting the inflammatory response. These results suggest that the P20 peptide decreased airway constriction and disrupted stress fibers through regulation of the actin cytoskeleton downstream of beta2AR. Thus, the P20 peptide may be a potential therapeutic for asthma refractory to beta-agonists.

The beta2-adrenoceptor agonist formoterol stimulates mitochondrial biogenesis.[Pubmed:22490378]

J Pharmacol Exp Ther. 2012 Jul;342(1):106-18.

Mitochondrial dysfunction is a common mediator of disease and organ injury. Although recent studies show that inducing mitochondrial biogenesis (MB) stimulates cell repair and regeneration, only a limited number of chemicals are known to induce MB. To examine the impact of the beta-adrenoceptor (beta-AR) signaling pathway on MB, primary renal proximal tubule cells (RPTC) and adult feline cardiomyocytes were exposed for 24 h to multiple beta-AR agonists: isoproterenol (nonselective beta-AR agonist), (+/-)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL 37344) (selective beta(3)-AR agonist), and formoterol (selective beta(2)-AR agonist). The Seahorse Biosciences (North Billerica, MA) extracellular flux analyzer was used to quantify carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled oxygen consumption rate (OCR), a marker of maximal electron transport chain activity. Isoproterenol and BRL 37244 did not alter mitochondrial respiration at any of the concentrations examined. Formoterol exposure resulted in increases in both FCCP-uncoupled OCR and mitochondrial DNA (mtDNA) copy number. The effect of formoterol on OCR in RPTC was inhibited by the beta-AR antagonist propranolol and the beta(2)-AR inverse agonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol hydrochloride (ICI-118,551). Mice exposed to formoterol for 24 or 72 h exhibited increases in kidney and heart mtDNA copy number, peroxisome proliferator-activated receptor gamma coactivator 1alpha, and multiple genes involved in the mitochondrial electron transport chain (F0 subunit 6 of transmembrane F-type ATP synthase, NADH dehydrogenase subunit 1, NADH dehydrogenase subunit 6, and NADH dehydrogenase [ubiquinone] 1beta subcomplex subunit 8). Cheminformatic modeling, virtual chemical library screening, and experimental validation identified nisoxetine from the Sigma Library of Pharmacologically Active Compounds and two compounds from the ChemBridge DIVERSet that increased mitochondrial respiratory capacity. These data provide compelling evidence for the use and development of beta(2)-AR ligands for therapeutic MB.

Attenuated aortic vasodilation and sympathetic prejunctional facilitation in epinephrine-deficient mice: selective impairment of beta2-adrenoceptor responses.[Pubmed:25161169]

J Pharmacol Exp Ther. 2014 Nov;351(2):243-9.

It has been suggested that there is a link between epinephrine synthesis and the development of beta2-adrenoceptor-mediated effects, but it remains to be determined whether this development is triggered by epinephrine. The aim of this study was to characterize beta-adrenoceptor-mediated relaxation and facilitation of norepinephrine release in the aorta of phenylethanolamine-N-methyltransferase-knockout (Pnmt-KO) mice. Catecholamines were quantified by reverse-phase high-performance liquid chromatography-electrochemical detection. Aortic rings were mounted in a myograph to determine concentration-response curves to selective beta1- or beta2-adrenoceptor agonists in the absence or presence of selective beta1- or beta2-adrenoceptor antagonists. Aortic rings were also preincubated with [(3)H]norepinephrine to measure tritium overflow elicited by electrical stimulation in the presence of increasing concentrations of nonselective beta- or selective beta2-adrenoceptor agonists. beta2-Adrenoceptor protein density was evaluated by Western blotting and beta2-adrenoceptor localization by immunohistochemistry. Epinephrine is absent in Pnmt-KO mice. The potency and the maximal effect of the beta2-adrenoceptor agonist terbutaline were lower in Pnmt-KO than in wild-type (WT) mice. The selective beta2-adrenoceptor antagonist ICI 118,551 [(+/-)-erythro-(S*,S*)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylet hyl)amino]-2-butanol hydrochloride] antagonized the relaxation caused by terbutaline in WT but not in Pnmt-KO mice. Isoproterenol and terbutaline induced concentration-dependent increases in tritium overflow in WT mice only. beta2-Adrenoceptor protein density was decreased in membrane aorta homogenates of Pnmt-KO mice, and this finding was supported by immunofluorescence confocal microscopy. In conclusion, epinephrine is crucial for beta2-adrenoceptor-mediated vasodilation and facilitation of norepinephrine release. In the absence of epinephrine, beta2-adrenoceptor protein density was decreased in aorta cell membranes, thus potentially hindering its functional activity.

Norepinephrine responses in rat renal and femoral veins are reinforced by vasoconstrictor prostanoids.[Pubmed:26141930]

Vascul Pharmacol. 2015 Sep;72:93-100.

Norepinephrine (NE) responses are larger in renal and femoral veins compared to phenylephrine (PE). These differences may be due to the subtypes of adrenoceptor involved in these responses or to the involvement of local modulatory mechanisms. Therefore, the present study investigated in organ bath the adrenoceptor subtypes involved in the NE and PE responses in both renal and femoral veins as well as the influence of local mechanisms related to NO and to prostanoids upon these responses. The obtained data showed that the NE responses in these veins were not significantly modified by the selective inhibition of beta1 or beta2-adrenoceptors as well as AT1 or AT2 receptors. However, yohimbine reduced the NE Rmax in renal veins and, in parallel, right shifted the NE concentration-response curves in femoral veins. In both veins, prazosin reduced the NE Rmax and the clonidine induced a measurable contraction. The endothelium removal attenuated the NE responses in femoral veins, thereby abolishing the differences of NE and PE responses. Furthermore, the NE responses in renal and femoral veins were attenuated by indomethacin, which suppressed the statistical difference in relation to the PE response. In conclusion, a synergism between alpha1- and alpha2-adrenoceptors is essential to assure full NE contractile responses in both renal and femoral veins. Thus, by acting simultaneously in these adrenoceptors, NE induces more pronounced contractile responses, in comparison to PE, not only in renal but also in femoral veins. Moreover, this pronounced NE response in both renal and femoral veins appears to involve endothelium-derived vasoconstrictor prostanoids.

Function and regulation of the beta 3-adrenoceptor.[Pubmed:8979772]

Trends Pharmacol Sci. 1996 Oct;17(10):373-81.

The cloning, sequencing and expression in model systems of the previously unidentified beta 3-adrenoceptor recently led to an extensive functional characterization. Ligand binding and adenylate cyclase activation studies helped define a specific profile that is quite distinct from that of the beta 1- and beta 2-adrenoceptors, but strongly reminiscent of most of the 'atypical' beta-adrenoceptor-mediated responses reported in earlier pharmacological studies. More recently, a naturally occurring variation in the human beta 3-adrenoceptor has been correlated with hereditary obesity and with increased dynamic capacity to add on weight and develop non-insulin dependent diabetes in Western obese patients. Donny Strosberg and France Pietri-Rouxel describe how results now provide a consistent picture of an important role for the human beta 3-adrenoceptor in the regulation of lipid metabolism and as an obvious target for drugs to treat some forms of obesity and diabetes.

Beta 2- but not beta 3-adrenoceptors mediate prejunctional inhibition of non-adrenergic non-cholinergic contraction of guinea pig main bronchi.[Pubmed:7796855]

Eur J Pharmacol. 1995 Mar 6;275(2):199-206.

We studied the effects of selective beta-adrenoceptor agonists on the cholinergic and non-adrenergic non-cholinergic (excitatory NANC) contractions elicited by electrical field stimulation of guinea pig main bronchi in vitro. Addition of the selective beta 2-adrenoceptor agonists, fenoterol and salbutamol, and the selective beta 3-adrenoceptor agonist, BRL 37344 (4-[2-[(2-hydroxy-2-(3-chlor-phenyl)ethyl)amino]-propyl]-phenoxyac etic acid), induced a dose-dependent inhibition of the cholinergic contraction (pD2 7.89, 6.71 and 4.56, respectively) and the excitatory NANC response (pD2 9.11, 8.16 and 7.42, respectively). Fenoterol- and BRL 37344-induced inhibition of the excitatory NANC response was blocked with high potency (pKB 8.77 and 9.07, respectively) by the selective beta 2-adrenoceptor antagonist, ICI 118,511 (erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamino)-but an-2-ol). A comparable contraction induced by neurokinin A (2 or 5 nM) was also inhibited by fenoterol, salbutamol and BRL 37344, but at significantly higher concentrations than for the inhibition of the excitatory NANC response (pD2 8.72, 7.56 and 6.66, respectively). Such a preferential inhibition of electrical field stimulation- versus agonist-induced effects was not observed for cholinergic contractions (pD2 versus methacholine-induced tone 7.86, 6.93 and 5.10, respectively). The results clearly exclude the involvement of beta 3-adrenoceptors in these responses. Furthermore they show that beta 2-adrenoceptors are involved in the prejunctional inhibition of excitatory NANC contractions, presumably via modulation of tachykinin release from sensory nerves, and solely in the postjunctional inhibition of cholinergic contractions.

The pharmacology of a beta 2-selective adrenoceptor antagonist (ICI 118,551).[Pubmed:6191142]

J Cardiovasc Pharmacol. 1983 May-Jun;5(3):430-7.

While specific antagonists of the beta 1-adrenoceptor, such as atenolol and betaxolol, are widely available, a potent specific antagonist selective for the beta 2-adrenoceptor has yet to be described. Previously described beta 2-selective antagonists such as butoxamine, H 35/25, and IPS 339 are lacking in potency, specificity, or appropriate beta 2-selectivity. ICI 118,551 [erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol] possesses a high degree of selectivity and specificity for the beta 2-adrenoceptor. The affinity of propranolol and ICI 118,551 for beta-adrenoceptors has been determined by comparing their antagonist potencies, expressed as pA2 values, against the actions of isoproterenol on the guinea pig atrium and uterus. ICI 118,551 had a higher affinity for the uterine beta 2-receptor than did propranolol (pA2 9.26 and 8.64, respectively) but a lower affinity for the atrial beta 1-receptor (pA2 7.17 and 8.30, respectively). Thus, the beta 2/ beta 1-selectivity ratios, in vitro, were 123 for ICI 118,551 and 2.2 for propranolol. The potency and selectivity of ICI 118,551 and atenolol on the chronotropic and vasodilator actions of isoproterenol were compared in anaesthetised dogs. The apparent K' B values at the vascular beta-adrenoceptor were 2.1 micrograms/kg for ICI 118,551 and 253 micrograms/kg for atenolol, and the potency ratio for antagonism of vascular versus atrial actions of isoproterenol was greater than 250:1. In regard to ancillary pharmacological properties, ICI 118,551 has no partial agonist activity but has a membrane-stabilising action similar to that of propranolol.

ICI 118,551 (hydrochloride) is a highly selective β2 adrenergic receptor antagonist, with Kis of 0.7, 49.5 and 611 nM for β2, β1 and β3 receptors, respectively.

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