Β3-adrenoceptor Agonist Mirabegron Research Articles

Ligand-Receptor Interactions and Structure-Function Relationships in Off-Target Binding of the β3-Adrenergic Agonist Mirabegron to α1A-Adrenergic Receptors.

The β3-adrenoceptor agonist mirabegron is available for the treatment of storage symptoms of overactive bladder, including frequency, urgency, and incontinence. The off-target effects of mirabegron include binding to α1-adrenoceptors, which are central in the treatment of voiding symptoms. Here, we examined the structure-function relationships in the binding of mirabegron to a cryo-electron microscopy structure of α1A. The binding was simulated by docking mirabegron to a 3D structure of a human α1A-adrenoceptor (7YMH) using Autodock Vina. The simulations identified two binding states: slope orientation involving 10 positions and horizontal binding to the receptor surface involving 4 positions. No interactions occurred with positions constituting the α1A binding pocket, including Asp-106, Ser-188, or Phe-312, despite the positioning of the phenylethanolamine moiety in transmembrane regions close to the binding pocket by contact with Phe-288, -289, and Val-107. Contact with the unique positions of α1A included the transmembrane Met-292 during slope binding and exosite Phe-86 during horizontal binding. Exosite binding in slope orientation involved contact of the anilino part, rather than the aminothiazol end, to Ile-178, Ala-103, and Asn-179. In conclusion, contact with Met-292 and Phe-86, which are unique positions of α1A, accounts for mirabegron binding to α1A. Because of its lack of interactions with the binding pocket, mirabegron has lower affinity compared to α1A-blockers and no effects on voiding symptoms.

In vitro effects of β3-adrenoceptor agonist mirabegron on the human ureter.

This study aimed to investigate the effect of mirabegron, a β3-adrenoceptor agonist with widespread clinical use for treating overactive bladder disease, on isolated healthy human ureter strips. This was a prospective study employing a series of in vitro organ bath experiments using ureteral tissues of kidney grafts from 10 healthy donors. The ureteral strips were subjected to cumulative mirabegron concentrations (10-9-10-4.5 M). Effects on frequency or amplitude of spontaneous, 10 mM KCl- or EFS-induced contractions were evaluated. Mirabegron decreased the frequency of spontaneous ureteric contraction in a concentration-dependent manner. Statistically significant decrease in the frequency of spontaneous contraction was observed at 10-8-10-4.5 M. In 10 mM KCl medium, statistically significant change in frequency was observed at 10-9-10-4.5 M. Statistically significant decrease in the amplitudes of spontaneous contraction was observed at 10-7-10-4.5 M. In a 10 mM KCl medium, statistically significant change in amplitudes was observed at 10-8-10-4.5 M. Mirabegron reduced the amplitude and frequency of human ureter activity in in vitro organ bath studies. This effect was achieved in a dose-dependent manner on isolated tissue strips. Although monotherapy with mirabegron remains uncertain, this study has the potential to elucidate the mechanism underlying the effectiveness of mirabegron, particularly in combination therapy for ureteral stones.

Adrenoceptors in GtoPdb v.2023.3

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [64, 194]. Adrenoceptors, α1 The three α1-adrenoceptor subtypes α1A, α1B and α1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. -(-)phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for α1- relative to α2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin- QAPB) are used to examine cellular localisation of α1-adrenoceptors. α1-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds being α1A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (doxazosin, terazosin). The α1- and β2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are α1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension. Adrenoceptors, α2The three α2-adrenoceptor subtypes α2A, α2B and α2C are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for α2- relative to α1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of the α2A-adrenoceptor. Multiple mutations of α2-adrenoceptors have been described, some associated with alterations in function. Presynaptic α2-adrenoceptors regulate many functions in the nervous system. The α2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [33] and veterinary medicine and has sympatholytic and anxiolytic properties. The α2-adrenoceptor antagonist mirtazapine is used as an anti-depressant. The α2B subtype appears to be involved in neurotransmission in the spinal cord and α2C in regulating catecholamine release from adrenal chromaffin cells. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools. Adrenoceptors, β The three β-adrenoceptor subtypes β1, β2 and β3 are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for β-adrenoceptors relative to α1- and α2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively selective antagonists for β1- and β2- relative to β3-adrenoceptors. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for β1- relative to β2-adrenoceptors. Pharmacological differences exist between human and mouse β3-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human β3-adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate human β3-adrenoceptors [88]. β3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at β3-adrenoceptors, but does not discriminate between the three β- subtypes [332] whereas L-748337 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label β1- and β2- adrenoceptors and β3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with β1- and β2-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track β-adrenoceptors at the cellular level [8]. Somewhat selective β1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. β1-Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol) but also in combination with other treatments to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol) [528]. Cardiac failure is also treated with carvedilol that blocks β1- and β2-adrenoceptors, as well as α1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting β2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation β-adrenoceptor antagonists (propranolol) block both β1- and β2-adrenoceptors and there are no β2-adrenoceptor-selective antagonists used therapeutically. The β3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest that β-adrenoceptor antagonists can reduce metastasis in certain types of cancer [197].

Adrenoceptors in GtoPdb v.2023.1

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [64, 194]. Adrenoceptors, α1 The three α1-adrenoceptor subtypes α1A, α1B and α1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. -(-)phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for α1- relative to α2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin- QAPB) are used to examine cellular localisation of α1-adrenoceptors. α1-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds being α1A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (doxazosin, terazosin). The α1- and β2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are α1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension. Adrenoceptors, α2 The three α2-adrenoceptor subtypes α2A, α2B and α2C are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for α2- relative to α1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of the α2A-adrenoceptor. Multiple mutations of α2-adrenoceptors have been described, some associated with alterations in function. Presynaptic α2-adrenoceptors regulate many functions in the nervous system. The α2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [33] and veterinary medicine and has sympatholytic and anxiolytic properties. The α2-adrenoceptor antagonist mirtazapine is used as an anti-depressant. The α2B subtype appears to be involved in neurotransmission in the spinal cord and α2C in regulating catecholamine release from adrenal chromaffin cells. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools. Adrenoceptors, β The three β-adrenoceptor subtypes β1, β2 and β3 are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for β-adrenoceptors relative to α1- and α2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively selective antagonists for β1- and β2- relative to β3-adrenoceptors. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for β1- relative to β2-adrenoceptors. Pharmacological differences exist between human and mouse β3-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human β3-adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate human β3-adrenoceptors [88]. β3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at β3-adrenoceptors, but does not discriminate between the three β- subtypes [332] whereas L-748337 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label β1- and β2- adrenoceptors and β3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with β1- and β2-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track β-adrenoceptors at the cellular level [8]. Somewhat selective β1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. β1-Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol) but also in combination with other treatments to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol) [528]. Cardiac failure is also treated with carvedilol that blocks β1- and β2-adrenoceptors, as well as α1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting β2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation β-adrenoceptor antagonists (propranolol) block both β1- and β2-adrenoceptors and there are no β2-adrenoceptor-selective antagonists used therapeutically. The β3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest that β-adrenoceptor antagonists can reduce metastasis in certain types of cancer [197].

β3 adrenoceptor agonist mirabegron protects against right ventricular remodeling and drives Drp1 inhibition.

The right ventricular (RV) function determines the prognosis of patients with pulmonary hypertension (PH). Metabolic disorders have been observed in the RV myocardium in PH. Activation of the β3 adrenoceptor improves cardiac function and restores cardiac metabolic efficiency in rodents with heart failure; however, its role in the RV remains uncertain. Experimental PH was induced by monocrotaline (MCT) in rats. Mirabegron, a selective β3 adrenoceptor agonist, was given to MCT rats daily from the day after MCT injection at the dose of 10 mg/kg. In vivo echocardiography and RV catheterization were performed to assess RV hemodynamics, structure, and function. RV fibrosis and hypertrophy were assessed by Sirius Red (SR) and wheat germ agglutinin (WGA) staining respectively. Western blotting was performed to examine the markers of RV fibrosis and hypertrophy, as well as the levels of the key molecules and their phosphorylated forms. The molecular changes were confirmed in the cardiac hypertrophy model of angiotensin II (Ang II) treated H9c2 cardiomyocytes using western blotting. The overloaded RV had increased β3 adrenoceptor expression, which was further increased by mirabegron. Mirabegron reduced RV pressure and reduced RV structural and functional deterioration in MCT rats. Mirabegron decreased cardiac fibrosis and hypertrophy in the overloaded RV. Mirabegron suppressed dynaminrelated protein 1 (Drp1) and promoted AMP-activated protein kinase (AMPK) signaling in the overloaded RV and Ang II treated cardiomyocytes. The β3 adrenoceptor agonist mirabegron reduced RV hypertrophy and fibrosis in PH rats. The treatment effect involved Drp1 inhibition and AMPK activation.

β1- and β1/β2-adrenergic receptor antagonists block 6-nitrodopamine-induced contractions of the rat isolated epididymal vas deferens.

6-Nitrodopamine (6-ND) is an endogenous modulator of the contractility in the rat isolated epididymal vas deferens (RIEVD) and considered to be the main peripheral mediator of the emission process. Use of selective and unselective β-adrenergic receptor antagonists has been associated with ejaculatory failure. Here, the effects of selective β1- and β1/β2-adrenergic receptor antagonists on RIEVD contractions induced by 6-ND, dopamine, noradrenaline, adrenaline, and electric-field stimulation (EFS) were investigated. The selective β1-adrenergic receptor antagonists atenolol (0.1 and 1µM), betaxolol (1µM), and metoprolol (1µM) and the unselective β1/β2-adrenergic receptor antagonists propranolol (1 and 10µM) and pindolol (10µM) caused significant rightward shifts of the concentration-response curve to 6-ND (pA2 6.41, 6.91, 6.75, 6.47, and 5.74; for atenolol, betaxolol, metoprolol, propranolol, and pindolol), but had no effect on dopamine-, noradrenaline-, and adrenaline-induced contractions. The effects of selective β1- and β1/β2-adrenergic receptor antagonists at a higher concentration (atenolol 1µM, betaxolol 1µM, metoprolol 1µM, propranolol 10µM, and pindolol 10µM) also reduced the EFS-induced RIEVD contractions in control, but not in RIEVD obtained from L-NAME-treated animals. The selective β1-adrenoceptor agonist RO-363, the selective β2-adrenoceptor agonist salbutamol, and the selective β3-adrenoceptor agonist mirabegron, up to 300µM, had no effect on the RIEVD tone. The results demonstrate that β1- and β1-/β2-adrenoceptor receptor antagonists act as 6-ND receptor antagonists in RIEVD, further confirming the main role of 6-ND in the RIEVD contractility.

Adrenoceptors in GtoPdb v.2021.3

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [60, 186]. Adrenoceptors, α1 The three α1-adrenoceptor subtypes α1A, α1B and α1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. -(-)phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for α1- relative to α2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin- QAPB) are used to examine cellular localisation of α1-adrenoceptors. α1-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds being α1A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (doxazosin, terazosin). The α1- and β2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are α1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension. Adrenoceptors, α2 The three α2-adrenoceptor subtypes α2A, α2B and α2C are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for α2- relative to α1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of the α2A-adrenoceptor. Multiple mutations of α2-adrenoceptors have been described, some associated with alterations in function. Presynaptic α2-adrenoceptors regulate many functions in the nervous system. The α2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [31] and veterinary medicine and has sympatholytic and anxiolytic properties. The α2-adrenoceptor antagonist mirtazapine is used as an anti-depressant. The α2B subtype appears to be involved in neurotransmission in the spinal cord and α2C in regulating catecholamine release from adrenal chromaffin cells. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools. Adrenoceptors, β The three β-adrenoceptor subtypes β1, β2 and β3 are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for β-adrenoceptors relative to α1- and α2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively selective antagonists for β1- and β2- relative to β3-adrenoceptors. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for β1- relative to β2-adrenoceptors. Pharmacological differences exist between human and mouse β3-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human β3-adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate human β3-adrenoceptors [88]. β3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at β3-adrenoceptors, but does not discriminate between the three β- subtypes [320] whereas L-748337 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label β1- and β2- adrenoceptors and β3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with β1- and β2-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track β-adrenoceptors at the cellular level [8]. Somewhat selective β1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. β1-Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol) but also in combination with other treatments to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol) [507]. Cardiac failure is also treated with carvedilol that blocks β1- and β2-adrenoceptors, as well as α1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting β2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation β-adrenoceptor antagonists (propranolol) block both β1- and β2-adrenoceptors and there are no β2-adrenoceptor-selective antagonists used therapeutically. The β3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest that β-adrenoceptor antagonists can reduce metastasis in certain types of cancer [189].

Effect of oxybutynin patch versus mirabegron on nocturia-related quality of life in female overactive bladder patients: A multicenter randomized trial.

To investigate the effect of oxybutynin patch versus β3-adrenoceptor agonist mirabegron on nocturia-related quality of life in female overactive bladder patients. In the present study, female overactive bladder patients were enrolled. The patients were randomly allocated into two groups: the oxybutynin patch group and the mirabegron group. Each of the drugs was given for 8weeks. The changes in the total Nocturia Quality of Life Questionnaire score were evaluated. Parameters on a frequency volume chart were also evaluated. In total, 100 patients (51 oxybutynin patch, 49 mirabegron) were treated with oxybutynin patch or mirabegron. The changes in the Nocturia Quality of Life Questionnaire score 4weeks after administration were 3.8±18.6 and 8.7±13.1 with the oxybutynin patch group and the mirabegron group, respectively, which were significantly higher than those at the baseline. Furthermore, the changes in the Nocturia Quality of Life Questionnaire score 8weeks after administration were 4.3±16.5 and 7.7±12.3, respectively. A statistical difference was seen only in the mirabegron group. Regarding the Nocturia Quality of Life Questionnaire subscores, oxybutynin patch and mirabegron significantly improved the Nocturia Quality of Life Questionnaire bother/concern subscore 4 and 8weeks after administration, whereas the Nocturia Quality of Life Questionnaire sleep/energy subscore was not significantly improved in each period. Eight weeks after administration, 24-h frequency, 24-h urinary urgency and mean voided urine volume were improved in both groups statistically. The oxybutynin patch improves quality of life, focusing mainly on nocturia by improving the bother/concern subscores of the Nocturia Quality of Life Questionnaire in the short term.

Possible Involvement of Muscarinic Receptor Blockade in Mirabegron Therapy for Patients with Overactive Bladder.

The selective β 3-adrenoceptor agonist mirabegron, an established alternative to antimuscarinic therapy for patients with overactive bladder, induces additional effects against receptors, transporters, and hepatic enzymes. The present study aimed to elucidate the effects of mirabegron on muscarinic receptors in the rat bladder using radioligand binding and functional assays. Mirabegron (0.1-100 μM) inhibited specific [N-methyl-3H]scopolamine methyl chloride binding in the bladder and other tissues of rats in a concentration-dependent manner. Binding affinity in the bladder was similar to that in the heart and significantly higher than those in the submaxillary gland and brain. Mirabegron induced the concentration-dependent relaxation of carbachol-induced contractions in the rat isolated bladder. Further analyses using a two-site model revealed that the relative quantities of high- and low-affinity components for mirabegron were 44.5% and 55.5%, respectively. Respective pEC50 values were 7.06 and 4.97. Based on the receptor binding affinity and pharmacokinetics of mirabegron, muscarinic receptor occupancy in the human bladder for 24 hours after the administration of a single oral dose of 50 mg mirabegron was 37%-76%. The present results demonstrate for the first time that mirabegron may relax the detrusor smooth muscle not only by β 3-adrenoceptor activation but also muscarinic receptor blockade. SIGNIFICANCE STATEMENT: Mirabegron, the first selective β 3-adrenoceptor agonist, represents an alternative to antimuscarinic agents for management of overactive bladder (OAB). The present study aimed to clarify whether mirabegron directly binds to muscarinic receptors and affects cholinergic agonist-induced contractions in rat urinary bladder and to predict muscarinic receptor occupancy in human bladder after oral administration of mirabegron. The results demonstrated that mirabegron therapy for patients with OAB may be due not only to β 3-adrenoceptor activation but also muscarinic receptor blockade.

Adrenoceptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [58], see also [180]. Adrenoceptors, α1α1-Adrenoceptors are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. phenylephrine, methoxamine and cirazoline are agonists and prazosin and cirazoline antagonists considered selective for α1- relative to α2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy PLprazosin- QAPB) are used to examine cellular localisation of α1-adrenoceptors. Selective α1-adrenoceptor agonists are used as nasal decongestants; antagonists to treat hypertension (doxazosin, prazosin) and benign prostatic hyperplasia (alfuzosin, tamsulosin). The α1- and β2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are α1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension and extrapyramidal effects.Adrenoceptors, α2 α2-Adrenoceptors are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for α2- relative to α1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There is species variation in the pharmacology of the α2A-adrenoceptor. Multiple mutations of α2-adrenoceptors have been described, some associated with alterations in function. Presynaptic α2-adrenoceptors regulate many functions in the nervous system. The α2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is used as a sedative and analgesic in human and veterinary medicine with sympatholytic and anxiolytic properties. The α2-adrenoceptor antagonist yohimbine has been used to treat erectile dysfunction and mirtazapine as an anti-depressant. The α2B subtype appears to be involved in neurotransmission in the spinal cord and α2C in regulating catecholamine release from adrenal chromaffin cells.Adrenoceptors, ββ-Adrenoceptors are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for β-adrenoceptors relative to α1- and α2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively β1 and β2 adrenoceptor-selective antagonists. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for β1- relative to β2-adrenoceptors. Pharmacological differences exist between human and mouse β3-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human β3-adrenoceptor whereas CGP 12177 and L 755507 activate human β3-adrenoceptors [88]. β3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at β3-adrenoceptors, but does not discriminate well between the three β- subtypes whereas L 755507 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label β1- and β2- adrenoceptors and β3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with β1- and β2-adrenoceptor antagonists. [3H]-L-748337 is a β3-selective radioligand [474]. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track β-adrenoceptors at the cellular level [8]. Somewhat selective β1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. β1-Adrenoceptor-preferring antagonists are used to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol), cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol). Cardiac failure is also treated with carvedilol that blocks β1- and β2-adrenoceptors, as well as α1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting β2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation β-adrenoceptor antagonists (propranolol) block both β1- and β2-adrenoceptors and there are no β2-adrenoceptor-selective antagonists used therapeutically. The β3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome.

Association of Mirabegron With the Risk of Arrhythmia in Adult Patients 66 Years or Older—A Population-Based Cohort Study

This population-based cohort study evaluates the risk of cardiac arrhythmia and other cardiovascular events in patients 66 years or older receiving the β3-adrenoceptor agonist mirabegron.

Mirabegron: A Review in Overactive Bladder Syndrome.

The first-in-class β3-adrenoceptor agonist mirabegron is indicated in the EU (Betmiga™), Japan (Betanis™) and several other countries for the management of overactive bladder (OAB) syndrome. Evidence for its use in this setting includes several large phase 3 trials. Compared with placebo, oral mirabegron for 12weeks reduced the frequency of micturition and generally also that of incontinence, with other benefits including reduced urgency, increased void volume and improved health related quality-of-life (HR-QOL). Mirabegron comparisons versus tolterodine are descriptive; however, in a 12-week powered comparison versus solifenacin in patients dissatisfied with antimuscarinic efficacy, mirabegron did not demonstrate noninferiority in reducing micturition frequency or significantly differ in terms of improving other urinary symptoms. Urinary and HR-QOL benefits of mirabegron were sustained over up to 52weeks of treatment and the drug was generally well tolerated, with a numerically lower incidence of dry mouth than antimuscarinics. Real-world data support the trial findings and indicate possible persistence and adherence benefits for mirabegron over antimuscarinics. Mirabegron use is not generally restricted by patient age, sex or antimuscarinic treatment status, although data in men (from a phase 4 study and phase 3 trial subanalyses) are variable; additional studies in older and male OAB patients are awaited with interest. Although further longer-term efficacy and tolerability data would be beneficial, current clinical evidence indicates that mirabegron provides an alternative to antimuscarinics for the management of OAB in adults, including those for whom antimuscarinics have proven unsuitable.

Micturition dysfunction in four-month old ovariectomized rats: Effects of testosterone replacement

AimsAndrogen deficiency has been implicated in urological complications of postmenopausal women. This study examined the effects of testosterone replacements on the lower urinary tract dysfunction in 4-month old ovariectomized (OVX) rats. Main methodsSprague-Dawley female rats were OVX bilaterally. Three months later, rats received single intramuscular injections of testosterone undecanoate. Cystometric study, and bladder and urethra smooth muscle reactivities were evaluated. Key findingsOvariectomy reduced by 65% (p<0.05) the serum testosterone levels. Testosterone replacement at 5mg/kg restored serum hormone levels to baseline, whereas 10mg/kg produced 14-fold higher testosterone levels. OVX rats exhibited significant increases of body weight, perigonadal fat and blood pressure, and reduced uterus weight, but none of these parameters were changed by testosterone replacements. OVX rats exhibited micturition dysfunction characterized by increases of basal pressure, threshold pressure, voiding frequency and post-voiding pressure. In addition, the bladder contractions induced by electrical-field stimulation (EFS) and carbachol were significantly reduced, whereas angiotensin II-induced urethral contractions were significantly increased in OVX rats. Testosterone replacement at 10mg/kg (but not at 5mg/kg) dose fully normalized the in vivo micturition dysfunction, as well as the in vitro bladder and urethral alterations. Testosterone (10mg/kg) also significantly potentiated the bladder relaxations induced by the β3-adrenoceptor agonist mirabegron. The protective effects of testosterone were not modified by concomitant treatment with the aromatase inhibitor letrozole (2.5mg/kg, 4weeks). SignificanceThe improvement of micturition dysfunction by testosterone replacement suggests that androgen therapy might be of therapeutic benefit for urological complications associated with post-menopause.

β3-Adrenoceptor agonists for overactive bladder syndrome: Role of translational pharmacology in a repositioning clinical drug development project.

β3-Adrenoceptor agonists were originally considered as a promising drug class for the treatment of obesity and/or type 2 diabetes. When these development efforts failed, they were repositioned for the treatment of the overactive bladder syndrome. Based on the example of the β3-adrenoceptor agonist mirabegron, but also taking into consideration evidence obtained with ritobegron and solabegron, we discuss challenges facing a translational pharmacology program accompanying clinical drug development for a first-in-class molecule. Challenges included generic ones such as ligand selectivity, species differences and drug target gene polymorphisms. Challenges that are more specific included changing concepts of the underlying pathophysiology of the target condition while clinical development was under way; moreover, a paucity of public domain tools for the study of the drug target and aspects of receptor agonists as drugs had to be addressed. Nonetheless, a successful first-in-class launch was accomplished. Looking back at this translational pharmacology program, we conclude that a specifically tailored and highly flexible approach is required. However, several of the lessons learned may also be applicable to translational pharmacology programs in other indications.

Persistence and adherence with the new beta-3 receptor agonist, mirabegron, versus antimuscarinics in overactive bladder: Early experience in Canada.

Antimuscarinics are the principal pharmacological treatment for overactive bladder (OAB), but frequently give rise to anticholinergic side effects, such as dry mouth, a factor leading to poor persistence. The β3-adrenoceptor agonist mirabegron is devoid of significant anticholinergic activity, while being effective in OAB. We evaluated persistence and adherence with mirabegron versus antimuscarinics over 12 months. We obtained retrospective claims from a Canadian Private Drug Plan database for patients 18 years old and over, with a first claim for mirabegron or antimuscarinics during a 6-month index period (April-September 2013). A 6-month look-back identified those with no prior claims for OAB medication (treatment-naïve) or ≥1 prior OAB drug (treatment-experienced). Time to end of persistence (≥30 day therapy gap or switch of therapy) was evaluated over 12 months; adherence with medication (medication possession ratio) was also measured. Persistence data from 19 485 patients (74% female, 92% naïve, 19.9% aged ≥65 years) showed that for experienced patients the median number of days on mirabegron was 299 days, compared with a range of 96 to 242 days for the different antimuscarinics; for naïve patients, it was 196 versus 70 to 100 days, respectively. Persistence at 12 months was for mirabegron 39% versus 14% to 35% for antimuscarinics, (experienced) and 30% mirabegron versus 14% to 21% antimuscarinics, (naïve). Patients taking mirabegron demonstrated statistically significantly greater adherence than those taking antimuscarinics. Patients who received mirabegron remained longer on treatment than those treated with antimuscarinics, and had higher 12-month persistence and adherence rates.

Overactive Bladder and the β3-Adrenoceptor Agonists: Current Strategy and Future Prospects.

Overactive bladder (OAB) is a clinical syndrome describing the symptom complex of urgency, with or without urgency incontinence, and is usually associated with frequency and nocturia. It is a common, under-diagnosed and therefore under-treated condition that can have a detrimental effect on physical functioning and psychological well-being. Initial treatment of OAB includes lifestyle advice, behavioural modifications, bladder retraining and pelvic floor muscle training, usually in combination with antimuscarinic agents. The β3-adrenoceptor agonist mirabegron is the first of a new class of drugs that are now competing with the more established antimuscarinics for the treatment of OAB. Our review focuses on the mode of action, efficacy and tolerability of mirabegron. The place of β3-adrenoceptor agonists in the treatment algorithm of OAB is discussed, considering the adverse events associated with antimuscarinics. Drug therapy tailored to different population groups appears a promising future prospect. Development of other β3-adrenoceptor agonists is expected, and combination therapy regimens might revolutionise the treatment of OAB.

Clinical use of the β3 adrenoceptor agonist mirabegron in patients with overactive bladder syndrome.

Mirabegron is a β3 adrenoceptor agonist licensed for the treatment of overactive bladder symptoms, such as urinary urgency or urgency incontinence. β3 adrenoceptor activation causes detrusor muscle relaxation, but mirabegron may also act by binding other targets in the bladder, and it may also reduce activity in sensory nerves. Phase III clinical trials (SCORPIO, ARIES, and CAPRICORN) evaluated mirabegron at various doses, demonstrating reduction from baseline to endpoint in mean incontinence episodes and mean number of micturitions per 24 h (coprimary endpoints), along with health-related quality of life and a range of secondary measures. Efficacy was seen in many patients who had previously discontinued antimuscarinic therapy on the grounds of lack of efficacy or poor tolerability. Treatment emergent adverse effects were documented in a long-term study (TAURUS), mostly being of mild or moderate severity. The most frequent adverse effects were hypertension, dry mouth, constipation, and headache, with a lower incidence of dry mouth than for the antimuscarinic active comparator. Efficacy and safety are not substantially different in older patients. A urodynamic safety study in men showed no consistent effect on voiding function, but a small increase in postvoid residual. Use of mirabegron in combination with α-adrenergic blockers does not appear to increase adverse effects. Dose reduction is needed in people with severe renal failure, or moderate hepatic failure. Dose adjustment is not needed in relation to food intake. Ongoing research is evaluating the potential for combination therapy with antimuscarinics.

Prostaglandin E2 excitatory effects on rat urinary bladder: a comparison between the β-adrenoceptor modulation of non-voiding activity in vivo and micro-contractile activity in vitro.

Prostaglandin E2 (PGE2) is well known to modulate urinary bladder functions, but it is also thought to be involved in the pathophysiology of lower urinary tract dysfunctions, since high levels of PGE2 have been found in overactive bladder (OAB) patients. β-Adrenoceptors are major players in detrusor muscle relaxation, and the selective β3-adrenoceptor (AR) agonist mirabegron was recently approved for the treatment of overactive bladder (OAB). β-Adrenoceptor modulation of PGE2 excitatory effects on bladder detrusor muscle was investigated by i.v. mirabegron after intravesical PGE2 infusion in conscious rats. Non-voiding activity (NVA) was assessed under isovolumetric conditions. In addition, mirabegron and isoprenaline (0.01-10μM) were studied on PGE2-increased micro-contractile activity during isometric tension recordings of intact isolated bladder muscle strips. Our investigations showed that PGE2 dramatically increased NVA in vivo and spontaneous micro-contractions in vitro. In vivo administration of mirabegron (0.1, 0.3 and 3mg/kg) reduced PGE2-augmented NVA in dose-dependent manner, while the PGE2-increased micro-contractions in isolated bladder strips were poorly inhibited. Isoprenaline inhibited PGE2-augmented micro-contractions in a concentration-dependent manner and had a higher potency compared to mirabegron. The apparent pKB of 7.25 for metoprolol at the isoprenaline concentration-response curve for PGE2-augmented micro-contractions suggests a β1-AR-mediated.

Beta adrenergic modulation of spontaneous microcontractions and electrical field-stimulated contractions in isolated strips of rat urinary bladder from normal animals and animals with partial bladder outflow obstruction

Spontaneous microcontractions and electrical field stimulation (EFS)-evoked contractions in isolated rat bladder strips from normal and from 6weeks partial bladder outflow obstruction (pBOO) animals were studied to identify the potential site of action for the β3-adrenoceptor (AR) agonist mirabegron in detrusor overactivity in rats. For this, effects of the β-AR agonist isoprenaline and mirabegron were tested in presence or absence of selective antagonists for β-AR subtypes, namely CGP-20712A for β1-AR, ICI-118,551 for β2-AR, and L-748,337 for β3-AR. In detrusor strips from both normal and obstructed animals, EFS-induced contractions were weakly affected by isoprenaline and even less so by mirabegron. In contrast, microcontraction activity was more potently reduced by isoprenaline (pIC50 7.3; Emax ±85%), whereas mirabegron showed a small effect. In pBOO strips, concentration response curves for isoprenaline and mirabegron at inhibition of EFS and spontaneous microcontractions were similar to those in normal strips. Isoprenaline-induced inhibition of microcontractions and EFS was antagonized by the β1-AR antagonist, but not by the β2- and β3-AR antagonists. In the context of β3-AR-mediated bladder functions for mirabegron in other experiments, the current data question a role for effects at spontaneous microcontractions, or neurogenic detrusor stimulation in the mode of action for mirabegron in vivo, since functional bladder effects for mirabegron are reported to occur at much lower concentrations.

Efficacy of the β3-adrenoceptor Agonist Mirabegron for the Treatment of Overactive Bladder by Severity of Incontinence at Baseline: A Post Hoc Analysis of Pooled Data from Three Randomised Phase 3 Trials

The β3-adrenoceptor agonist mirabegron is approved for treatment of the symptoms of overactive bladder (OAB). Incontinence can be the most bothersome of OAB symptoms. Hence, we conducted a post hoc analysis of pooled data from three randomised, double-blind, placebo-controlled, 12-wk, phase 3 studies of mirabegron to evaluate the efficacy of mirabegron 50mg in incontinent OAB patients and in subgroups of patients stratified by severity of incontinence at baseline (an average of two or more [FAS-I≥2 subgroup] or four or more [FAS-I≥4 subgroup] incontinence episodes per 24h at baseline, where FAS-I is the full analysis set-incontinence population) and to determine correlations between measures of efficacy and disease severity. Mirabegron 50mg resulted in statistically significant improvements from baseline to final visit versus placebo in mean number of incontinence episodes, micturitions, and urgency episodes per 24h and mean volume voided per micturition in the pooled incontinent population and in the FAS-I≥2 and FAS-I≥4 subgroups. Treatment effect versus placebo for incontinence and urgency episodes increased with increasing severity of incontinence at baseline. Moderate correlations were seen between improvement in both frequency of incontinence episodes and micturitions and baseline incontinence and micturition frequency, respectively, with mirabegron 50mg and placebo. Patient summaryIncontinence can be the most bothersome of OAB symptoms; mirabegron 50mg once daily is effective for treatment of OAB symptoms in incontinent patients, and its effect increases with increasing severity of incontinence.