Agonist SR58611A Research Articles

Effect of β1 /β2 -adrenoceptor blockade on β3 -adrenoceptor activity in the rat cremaster muscle artery.

The physiological role of vascular β3 -adrenoceptors is not fully understood. Recent evidence suggests cardiac β3 -adrenoceptors are functionally effective after down-regulation of β1 /β2 -adrenoceptors. The functional interaction between the β3 -adrenoceptor and other β-adrenoceptor subtypes in rat striated muscle arteries was investigated. Studies were performed in cremaster muscle arteries isolated from male Sprague-Dawley rats. β-adrenoceptor expression was assessed through RT-PCR and immunofluorescence. Functional effects of β3 -adrenoceptor agonists and antagonists and other β-adrenoceptor ligands were measured using pressure myography. All three β-adrenoceptor subtypes were present in the endothelium of the cremaster muscle artery. The β3 -adrenoceptor agonists mirabegron and CL 316,243 had no effect on the diameter of pressurized (70 mmHg) cremaster muscle arterioles with myogenic tone, while the β3 -adrenoceptor agonist SR 58611A and the nonselective β-adrenoceptor agonist isoprenaline caused concentration-dependent dilation. In the presence of β1/2 -adrenoceptor antagonists nadolol (10 μM), atenolol (1 μM) and ICI 118,551 (0.1 μM) both mirabegron and CL 316,243 were effective in causing vasodilation and the potency of SR 58611A was enhanced, while responses to isoprenaline were inhibited. The β3 -adrenoceptor antagonist L 748,337 (1 μM) inhibited vasodilation caused by β3 -adrenoceptor agonists (in the presence of β1/2 -adrenoceptor blockade), but L 748,337 had no effect on isoprenaline-induced vasodilation. All three β-adrenoceptor subtypes were present in the endothelium of the rat cremaster muscle artery, but β3 -adrenoceptor mediated vasodilation was only evident after blockade of β1/2 -adrenoceptors. This suggests constitutive β1/2 -adrenoceptor activity inhibits β3 -adrenoceptor function in the endothelium of skeletal muscle resistance arteries.

Asymmetric hydrogenation of trisubstituted N-acetyl enamides derived from 2-tetralones using ruthenium-SYNPHOS catalysts: a practical synthetic approach to the preparation of β 3-adrenergic agonist SR58611A

The asymmetric hydrogenation of various trisubstituted enamides derived from 2-tetralones under mild reaction conditions using Ru-SYNPHOS catalysts is reported. This practical and clean method gives access to several chiral 2-aminotetralins derivatives in high isolated yields and enantiomeric excesses up to 95% depending on the substitution pattern of the aromatic ring and the nature of the amide moiety. In addition, the usefulness of the current method is demonstrated via a practical synthetic approach to the enantiomerically pure SR58611A compound, a potent and selective β 3-adrenergic receptor agonist.

Effect of β3-adrenoceptor agonist SR58611A on portal pressure of rats with compensated cirrhosis

Background/aims. Recent evidences suggest that the beta-adrenergic receptor β3 is involved in the regulation of the vascular tone in healthy animals. Selective agonists and antagonists for this receptor have only recently become available. We aimed at evaluating whether β3-adrenoceptor modulation influences systemic and splanchnic hemodynamics in cirrhotic rats without ascites.

The β3‐adrenoceptor agonist SR58611A ameliorates experimental colitis in rats

Beta(3)-adrenoceptor agonists protect against experimental gastric ulcers. We investigated the effects of the beta(3)-adrenoceptor agonist SR58611A on 2,4-dinitrobenzene sulphonic acid-induced colitis in rats and analysed the expression of beta(3)-adrenoceptors in the colonic wall. SR58611A was administered orally (1-10 mg kg(-1)) for 7 days, starting the day before induction of colitis. Colitis was assessed by macroscopic and histological scores, tissue myeloperoxidase activity, interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) levels. Reverse transcription-polymerase chain reaction and immunohistochemical analysis were used to examine the expression of beta(3)-adrenoceptors. SR58611A significantly reduced the severity of colitis as well as the tissue levels of TNF-alpha, IL-1beta and IL-6. Colitis was associated with a decreased expression of beta(3)-adrenoceptor mRNA in the mucosal/submucosal layer of distal colon and this reduction was not affected by SR58611A. Immunohistochemical analysis revealed beta(3)-adrenoceptors within the muscularis externa, in myenteric neurons and nerve fibres and in the submucosa. beta(3)-Adrenoceptor immunoreactivity was decreased in inflamed tissues compared to controls, particularly in the myenteric plexus; this reduction was counteracted by SR58611A. Amelioration of experimental colitis by the selective beta(3)-adrenoceptor agonist SR58611A suggests that beta(3)-adrenoceptors may represent a therapeutic target in gut inflammation.

Effects of the β 3-adrenoceptor (Adrb3) agonist SR58611A (amibegron) on serotonergic and noradrenergic transmission in the rodent: Relevance to its antidepressant/anxiolytic-like profile

SR58611A is a selective β 3-adrenoceptor (Adrb3) agonist which has demonstrated antidepressant and anxiolytic properties in rodents. The present study confirmed the detection of Adrb3 mRNA transcript in rodent brain sub-regions and evaluated the effect of SR58611A on serotonergic and noradrenergic transmission in rats and mice in an attempt to elucidate the mechanism(s) underlying these properties. SR58611A (3 and 10 mg/kg, p.o.) increased the synthesis of 5-HT and tryptophan (Trp) levels in several rodent brain areas (cortex, hippocampus, hypothalamus, striatum). Moreover, SR58611A (10 mg/kg, p.o.) increased the release of 5-HT assessed by in vivo microdialysis in rat prefrontal cortex. Systemic (3 mg/kg, i.v.) or chronic administration of SR58611A (10 mg/kg, p.o.), in contrast to fluoxetine (15 mg/kg, p.o.), did not modify the activity of serotonergic neurons in the rat dorsal raphe nucleus. The increase in 5-HT synthesis induced by SR58611A was not observed in Adrb3s knockout mice, suggesting a selective involvement of Adrb3s in this effect. SR58611A (3 and 10 mg/kg, p.o.) did not modify norepinephrine synthesis and metabolism but increased its release in rat brain. Repeated administration of SR58611A (10 mg/kg, p.o.) did not modify basal norepinephrine release in rat prefrontal cortex whereas it prevented its tail-pinch stress-induced enhancement similarly to reboxetine (15 mg/kg, p.o.). Finally SR58611A increased the firing rate of noradrenergic neurons in the rat locus coeruleus following systemic (3 mg/kg, i.v.) or local (0.01 and 1 μM) but not chronic (10 mg/kg, p.o.) administration. These results suggest that the anxiolytic- and antidepressant-like activities of SR58611A involve an increase of brain serotonergic and noradrenergic neurotransmissions, triggered by activation of Adrb3s.

Behavioral effects of the β3 adrenoceptor agonist SR58611A: Is it the putative prototype of a new class of antidepressant/anxiolytic drugs?

A large body of evidence corroborates the notion that deficiencies of serotonergic system are likely involved in the pathogenesis of both depression and anxiety. Activation of beta(3) adrenoceptors has been shown to increase brain tryptophan content suggesting an elevation of brain serotonin (5HT) synthesis. SR58611A is a selective beta(3) adrenergic agent possessing a profile of antidepressant activity in routine rodents' experimental models of depression. The present study was undertaken to evaluate in rodents the antidepressant properties of SR58611A and to assess its putative anxiolytic value in experimental models of depression and anxiety. Compared to the control group, SR58611A (0.1, 1, 5 or 10 mg/kg) caused a dose-dependent reduction in immobility of Wistar male rats in the forced swim test. The maximum dose appeared to be equivalent to an effective dose of clomipramine (50 mg/kg). In addition, acute injection of SR58611A induced in rats a dose-dependent decrease in grooming response to a novel environment (novelty-induced grooming test). For any dose, the effect was lower than that of diazepam (1 mg/kg). Chronic treatment with SR58611A resulted also in an increased social interaction time in the social interaction test without affecting motor activity of rats. Furthermore, similarly to diazepam a chronic treatment with the highest doses of SR58611A was followed by increased exploratory behavior in Swiss male mice exposed to the elevated plus maze test. These effects are mediated by beta(3) adrenoceptors since i.p. pretreatment with the selective beta(3) adrenoceptor antagonist SR59230A (5 mg/kg) blocked the effects of SR58611A. Finally, also the 5HT antagonist methysergide (2 mg/kg) prevented the antidepressant and anxiolytic-like activity of SR58611A indicating that 5HT transmission is strictly involved in its action.

Functional remodeling in post-myocardial infarcted rats: focus on beta-adrenoceptor subtypes

Cellular electrophysiological remodeling of the infarcted heart may lead to the deterioration of cardiac function and/or to arrhythmias. The present study was designed to characterize the functional expression of the hyperpolarization-activated current (I(f)) and its modulation by beta(1)-, beta(2)- and beta(3)-adrenoceptor (AR) subtypes, in patch-clamped ventricular myocytes isolated from the heart of post-myocardial infarcted (PMI) rats and sham-operated control (SHAM) rats. Maximum specific conductance of I(f) was significantly higher in left ventricular myocytes (LVM) from PMI rats compared to right ventricular myocytes from PMI rats as well as LVM and RVM from SHAM rats. All other basic properties of I(f) were similar. beta(1)AR stimulation with noradrenaline caused a rightward shift of V(H) in LVM from PMI rats which was significantly smaller (52.2%) than in LVM from SHAM rats. Incubation with pertussis toxin (PTX) largely restored the effect of beta(1)AR in PMI cells (86.6% vs. SHAM cells), but did not affect beta(1)AR response in SHAM cells. beta(2)AR response was significantly and equally increased by PTX-pretreatment (by 94% in SHAM and 87% in PMI cells). Conversely, beta(3)AR stimulation by the selective agonist SR 58611A caused a leftward shift of the activation curve which was significantly larger in PMI cells than in SHAM cells (P<0.01). beta(3)AR response was blunted by PTX-pretreatment, by incubation with N(G)-monomethyl-l-arginine acetate or by the selective beta(3)AR antagonist SR 59230A 1 microM. In conclusion, I(f) is significantly overexpressed in LVM from PMI rat hearts. In these cells, I(f) modulation by beta(1)AR is significantly depressed while beta(3)AR modulation is markedly enhanced, probably reflecting the increased activity of PTX-sensitive G(i) proteins in PMI cells.

ChemInform Abstract: Alternative Synthesis of the Chiral Atypical β‐Adrenergic Phenylethanolaminotetraline Agonist SR58611A Using Enantioselective Hydrogenation.

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Alternative synthesis of the chiral atypical β-adrenergicphenylethanolaminotetraline agonist SR58611A using enantioselective hydrogenation

We have developed an alternative synthesis of the atypical β-adrenergic phenylethanolaminotetraline agonist SR58611A. Two key intermediates have been synthesised involving enantioselective hydrogenation of an aminoketone and an enamide providing the corresponding amino alcohol and amide in >96 and >98 % ee respectively.

Effects of β 3-Adrenoceptor Agonist SR 58611A on Gastric Acid Secretion and Histamine Release in the Dog : Comparison with Ritodrine

1. The involvement of β 3 adrenoceptors in the control of gastric acid secretion and histamine release was investigated in the dog. 2. In conscious dogs, SR 58611A (0.0625–1.0 mg/kg/hr IV) dose dependently inhibited gastric acid secretion induced by pentagastrin. Maximal inhibition (40%) was obtained with the dose of 1 mg/kg. Ritodrine (1 mg/kg/hr IV) also induced a marked inhibition (85%) of gastric acid secretion stimulated by pentagastrin. 3. On 2-deoxy- d -glucose-stimulated acid secretion, both SR 58611A and ritodrine at 1 mg/kg/hr IV showed inhibitory effects. On these experiments, ritodrine, but not SR 58611A, significantly reduced plasma gastrin concentrations. 4. In anaesthetized dogs, histamine concentrations from gastrosplenic vein increased fivefold after the infusion of pentagastrin. SR 58611A (1 mg/kg/hr IV) did not significantly modify the stimulant effect of pentagastrin on histamine release. In contrast, ritodrine (1 mg/kg/hr IV) significantly inhibited histamine release induced by pentagastrin. 5. These data suggest that β 3 adrenoceptors may participate in the negative control of gastric acid secretion in the dog, probably through a histamine-independent mechanism.

Characterization of a beta 3-adrenoceptor stimulating gastrin and somatostatin secretions in rat antrum.

The beta 3-adrenoceptor (beta 3-AR) agonist SR-58611A {ethyl-[(7s)-7-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]5, 6,7,8-tetrahydronaphth-2-yl]oxyacetate hydrochloride} stimulated somatostatin and gastrin releases in isolated rat gastric antral epithelial cells. Stimulation was a concentration-dependent process with 50% effective concentrations of 2.7 +/- 1.1 and 3.8 +/- 1.9 nM compared with 209 +/- 71 and 230 +/- 51 nM for isoproterenol, respectively. It was inhibited by selective beta-AR antagonists with the following rank order of potency: SR-59230A 3-(2-ethylphenoxy)1-[(1S)-1,2,3,4-tetrahydronaphth- 1-ylamino]-(2S)-2-propranol oxalate; beta 3-AR antagonist > ICI-118551[erythro-(+/-)-1-(7-methylindan-4-yloxy)-3- isopropylaminobutan-2-ol-hydrochloride; beta 2-AR antagonist > CGP-20712A[(+/-)-[2-(3-carbarmoyl-4-hydroxyphenoxy)-et hyl- amino]-3-[4 (1-methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]- 2-propranol; beta 1-AR antagonist]. Furthermore, specific binding of 125I-cyanopindolol to the isolated cells was demonstrated and was displaced by the beta-AR antagonists according to the same rank order of potency and with apparent dissociation constants consistent with the 50% inhibitory concentrations for SR-58611A-stimulated somatostatin and gastrin releases. In addition, the presence of beta 3-AR mRNA was detected by reverse transcriptase polymerase chain reaction. These findings provide the first evidence for a gastric beta 3-AR mediating catecholamine stimulation of gastrin and somatostatin releases from antral cells.

Colonic and Cardiovascular Actions of the Atypical β‐Adrenergic Agonist SR 58611A in Rats

Inhibition of colonic myoelectric activity by the new atypical β‐adrenergic agonist SR 58611A and its cardiovascular effects were investigated in orally dosed unanesthetized rats. SR 58611A and the reference compound ritodrine caused dose‐related reduction of the long spike burst frequency of the proximal colon (respective ED50 values of 0.47 and 3.1 mg/kg); this was prevented by alprenolol but not by the β1‐ or β2‐selective adrenergic antagonists CGP 20712A and ICI 118,551. The minimal effective doses of SR 58611A and ritodrine raising heart rate were about 20 and 3 times their respective ED50 values for inhibition of colonie motility. Ritodrine, unlike SR 58611A, caused a dose‐dependent increase in heart rate. Blood pressure was not affected by either drug. There was partial tolerance to the intestinal effects of SR 58611A and ritodrine, which fell by about half after 4 days' treatment but no further after 8 days. In the animal model investigated, SR 58611A was less liable than ritodrine to induce cardiovascular side effects. It should thus be of prospective therapeutic interest for intestinal hypermotility disorders.