Agonisticky působící látky a vlivy
(S)-(-)-Pindolol
- Beta 3 partial agonist
- More active enantiomer of pindolol [4]
- (S)-1-(1H-indol-4-yloxy)-3-[(1-methylethyl)amino]-2-propanol
- 5-HT1A/1B receptor antagonist, with roughly equal affinity for each subtype
- A partial agonist at mouse and human beta 3-adrenoceptors
- More active enantiomer of pindolol. [4]
- Corradetti et al (1998)
- Antagonist properties of (-)-pindolol and WAY 100635 at somatodendritic and postsynaptic 5-HT1A receptors in the rat brain. Br.J.Pharmacol. 123 449 PMID: 9504386
- Kalkman (1989)
- Beta-Adrenoceptor blockade in rats enhances the ambulation induced by 5-HT1A receptor agonists. Eur.J.Pharmacol. 173 121 PMID: 2576226
- Walter et al (1984)
- Stimulant and blocking effects of optical isomers of pindolol on the sinoatrial node and trachea of guinea pig. Role of ß-adrenoceptor subtypes in the dissociation between blockade and stimulation. Naunyn Schmiedebergs Arch.Pharmacol. 327 159 PMID: 6092972 [4]
Arbutamine
- Elicit acute cardiovascular responses (cardiac stumulant)
- Similar to those produced by exercise
- To aid in diagnosing the presence or absence of coronary artery disease (CAD) in patients who cannot exercise adequately [3]
BRL 37344, sodium salt
- Beta 3 agonist [4]
- Chemical Name: (R*,R*)-(±)-4-[2-[(2-(3-Chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid, sodium salt
- Potent and selective beta3 adrenoceptor agonist (Ki values are 287, 1750 and 1120 nM for beta3, beta1 and beta2 receptors respectively) [4]
BRL37344
- B3AR agonists [12]
CGP 12177 hydrochloride
- Beta 3 partial agonist. ß1/ß2 antagonist [4]
- Chemical Name: 4-[3-[(1,1-Dimethylethyl)amino]2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride
- Formula C14H21N3O3.HCl
CL-316,243 disodium salt
- Cloning of the human beta(3)-AR has allowed for the development of novel compounds targeted specifically at the human receptor
- Clinical studies CL-316,243
- Highly selective beta 3 agonist
- (EC50 = 3 nM); > 10000-fold selective over beta 1 and beta 2 receptors.
- Increases brown adipose tissue thermogenesis and metabolic rate, and decreases blood insulin and glucose levels following oral administration in vivo. [4]
- Increase lipolysis, fat oxidation and insulin action in humans [1]
- Promising results in their ability to increase energy expenditure in humans following a single dose
- Do nor appear to be able to sustain their effects when administered chronically [1]
- Chemical Name: 5-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylic acid disodium salt
- Formula C20H18ClNNa2O7
- Bloom et al (1992)
- Disodium(R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316,243) A potent beta -adrenergic agonist virtually specific for beta 3 receptors. A promising antidiabetic and a J.Med.Chem. 35 3081 PMID: 1354264
- Woods et al (2001)
- Efficacy of the beta 3-adrenergic receptor agonist CL-316243 on experimental bladder hyperflexia and detrusor instability in the rat. J.Urol. 166 1142 PMID: 11490313
- Yoshida et al (1994)
- Anti-obesity and anti-diabetic effects of CL 316,243, a highly specific beta 3-adrenoceptor agonist, in yellow KK mice. Life Sci. 54 491 PMID: 8309351 [4]
Carvedilol
- Non-selectively binds B1 and B2AR, and has 100-fold lower affinity for B3AR
- no significant agonism or inverse agonism at B3AR [12]
Celiprolol
- Management of mild to moderate hypertension
- Effort-induced angina pectoris [3]
Dipivefrin
- Prodrug which is used as initial therapy for the control of intraocular pressure in chronic open-angle glaucoma [3]
Droxidopa
- Treatment of neurogenic orthostatic hypotension (NOH) associated with various disorders including
- Multiple System Atrophy
- Familial Amyloid Polyneuropathy
- Hemodialysis induced hypotension
- Parkinson's Disease
- Investigated for use/treatment in neurologic disorders, nephropathy, blood (blood forming organ disorders, unspecified), and dizzy/fainting spells [3]
L-755,507
- Very potent and selective ß3 partial agonist [4]
- Chemical Name: 4-[[(Hexylamino)carbonyl]amino]-N-[4-[2-[[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]phenyl]-benzenesulfonamide
- Potent ß3-adrenergic receptor partial agonist > 1000-fold selective over ß1- and ß2-adrenoceptors
- EC50 values are 0.43, 580 and > 10000 nM for activation of cloned human ß3-, ß1- and ß2-adrenoceptors respectively
- Stimulates lipolysis in rhesus adipocytes in vitro (EC50 = 3.9 nM)
- Enhances CRISPR-mediated homology-directed repair (HDR) efficiency 2-3-fold for large fragments and ~9-fold for point mutations, in human induced pluripotent stem cells (iPSCs) [5]
- A study of 4-acylaminobenzenesulfonamides in a cloned human beta 3 adrenergic receptor assay [6]
- Resulted in the discovery of n-hexylurea, L-755,507
- This 0.43 nM beta 3 agonist, which is > 440-fold selective over both beta 1 and beta 2 binding
- Is among the most potent human beta 3 agonists reported to date [6]
Zde nalézám další hypotetické spojení jak stimualce beta 3 AR může velmi přispívat k léčbě myeloproliferativních chorob (další souvislost viz OMIM - myelofibroza a velmi zajímavé postřehy na téma beta 3 AR) Od Dr. Landy vím, že v některých vzácných případech může u myeloproliferativních nemocí dojít i ke spontánní úzdravě zpětnou mutací/jinak u některých pacientů a k vymizení mutovaných klonů. Co kdyby za to mohla právě takováhle nějaká stimulace a šance na opravu by se dala podpořit nějakou takovouhle formou ??? Možná to není vlivem B3AR stimulace ale samotnou molekulou a jejími spec. vlastnostmi ?
3-pyridylethanolamine L-757,793
- Potent beta 3 AR agonist
- EC50 6.3 nM, 70% activation
- 1,300- and 500-fold selectivity over binding to the beta 1 and beta 2 ARs, respectively
- L-757,793 stimulated lipolysis in rhesus monkeys (ED50 0.2 mg/kg) with a maximum response equivalent to that elicited by isoproterenol [8]
Metoprolol
- Metoprolol and bisoprolol have a high affinity for B1AR
- no binding to B3AR [12]
- In dog with mitral regurgitation
- Metoprolol promoted the up-regulation of B3AR expression
- Its interaction with and activation of nNOS, followed by downstream cGMP production in specific membrane microdomains
- By protection of soluble guanylyl cyclase from oxidation under B1AR blockade
- Some of the cardioprotective effects of B1AR blockade
- May well result from enhanced expression and coupling of B3AR to NO/cGMP in the remodelled heart [12]
Mirabegron
- Beta-3 adrenergic agonist
- Indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency [3]
Ritobegron
Racepinephrine
- Indicated for temporary relief of mild symptoms of intermittent asthma [3]
Epinephrine
- Injection is indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis to stinging insects (e.g., order Hymenoptera, which include bees, wasps, hornets, yellow jackets and fire ants) and biting insects (e.g., triatoma, mosquitos), allergen immunotherapy, foods, drugs, diagnostic testing substances (e.g., radiocontrast media) and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis
- Injectable epinephrine is intended for immediate/urgent administration in patients, who are found to be at increased risk for anaphylaxis, including individuals with a history of anaphylaxis.
- Selection of the appropriate dosage strength is determined according to body weight [FDA label]
- Epinephrine's cardiac effects may be of use in restoring cardiac rhythm in cardiac arrest due to various causes but is not used in cardiac failure or in hemorrhagic, traumatic, or cardiogenic shock
- Epinephrine is used as a hemostatic agent.
- Treating mucosal congestion of hay fever, rhinitis, and acute sinusitis; to relieve bronchial asthmatic paroxysms
- In syncope due to complete heart block or carotid sinus hypersensitivity
- Symptomatic relief of serum sickness, urticaria, angioneurotic edema
- For resuscitation in cardiac arrest following anesthetic accidents
- In simple (open angle) glaucoma
- Relaxation of uterine musculature + inhibit uterine contractions
- Epinephrine injection can be utilized to prolong the action of local anesthetics
- Over the counter (OTC) agent for the intermittent symptoms of asthma, such as wheezing, tightness of chest and shortness of breath
- Maintenance of mydriasis during intraocular surgery
- Mainly used to treat patients in vasodilatory shock states such as septic shock and neurogenic shock and has shown a survival benefit over dopamine
- Used as a vasopressor medication for patients with critical hypotension [3]
Nebivolol
- B3AR agonist properties of nebivolol
- Conferred superior efficacy over metoprolol in protecting the infarcted mouse heart from adverse remodelling associated with
- Better preserved endothelial dependent vasodilatation
- Progenitor cells mobilization
- Functional recovery
- Nebivolol exerted a potent inhibition of NADPH oxidase activity and superoxide production in endothelial cells
- Was not sensitive to B1(or-2)AR blockade
- But abrogated by full B1-2-3 blockade
- Pointing to B3AR activation
- B3AR agonist properties of nebivolol
- Promote neoangiogenesis
- Could favour myocardial revascularization [12]
Dalo by se to využít při terapii lymfedémů ??
Naopak u nádorových onemocnění nebo diabetické retinopatie tohle asi uplně není žádoucí jev.
Svojí B3 aktivitou by mohl být vhodnou volbou u osteoporózy a možná i některých nemocí kostní dřeně.
Jaký vliv má konkrétně Nebivolol na depresi / náladu? Dělá depresi častěji nebo méně než ostatní beta-blokátory?
Jak vypadají NÚ Nebivololu na erekci v porovnání s ostatními blokátory ?
- Antioxidant effects of B3AR signalling may preserve the endothelium of the microvasculature from oxidative activation
- Ensuing recruitment of monocytes initiating subendothelial inflammation at the core of sustained endothelial dysfunction
Jaký vliv má tento lék na životní cyklus Chlamydia pneumonia ?
Jen aby to nepodporovalo šíření Chlamydiální infekce... Ale NO zabíjí Chlamydii. Cokoliv, co pomůže zvýšit endoteliální syntézu NO, by mohlo být v tomto směru dobré.
- Whether this will prevent chronic development of vascular atherosclerosis or chronic development of diastolic dysfunction initiating HFpEF42 will have to be tested with long-term interventions. [12]
Octopamine hydrochloride
- Invertebrate biogenic amine: activates ß3 adrenoceptors [4]
- Alternative Names: (±)-p-Octopamine, Epirenor, Norfen
- Chemical Name: alpha-(Aminomethyl)-4-hydroxybenzenemethanol hydrochloride
- Neurotransmitter, related to noradrenalin
- Stimulates lipolysis in mammalian adipocytes via activation of beta3 receptors
- Dual effect on glucose transport in adipocytes:
- Inhibits transport via beta 3 receptor activation
- But stimulates transport when oxidized by MAO
- Activates human alpha2A receptors, inhibiting subsequent cAMP production [4]
Pindolol
- Beta 3 partial agonist [4]
- Chemical Name: 1-(1H-Indol-4-yloxy)-3-[(1-methylethyl)amino]-2-propanol
- 5-HT1A/1B receptor antagonist
- Roughly equal affinity for each subtype
- A partial agonist at mouse and human beta 3-adrenoceptors [4]
Ritobegron
- It acts by relaxing the detrusor muscle during the storage phase of the urinary bladder by activation of beta-3 adrenergic receptors,
- Thereby increasing bladder capacity (FDA 2012)
- Effect of beta-3 adrenergic receptor agonists is through inhibition of the bladder afferent nerves,
- Thereby improving the symptom of urgency, which, as mentioned, is the key symptom in the diagnosis and monitoring response of OAB [11]
SR 58611A hydrochloride - amibegron
- Beta 3 agonist; displays anxiolytic and antidepressant effects [4]
- SR 58611A hydrochloride
- Chemical Name: [[(7S)-7-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-5,6,7,8-tetrahydro-2-naphthalenyl]ox]yacetic acid ethyl ester hydrochloride
- Selective beta3-adrenergic receptor agonist.
- Displays both anxiolytic and antidepressant effects in rodent models
- Orally active and brain penetrant.
- Formula C22H26ClNO4.HCl
- Consoli et al (2007)
- Behavioral effects of the beta3 adrenoceptor agonist SR58611A: is it the putative prototype of a new class of antidepressant/anxiolytic drugs? Eur.J.Pharmacol 573 139 PMID: 17669397
- Claustre et al (2008)
- Effects of the beta3-adrenoceptor (Adrb3) agonist SR58611A (amibegron) on serotonergic and noradrenergic transmission in the rodent: relevance to its antidepressant/anxiolytic-like profile. Neuroscience 156 353 PMID: 18691638
- Stemmelin et al (2008)
- Stimulation of the beta3-adrenoceptor as a novel treatment strategy for anxiety and depressive disorders. Neuropsychopharmacology 33 574 PMID: 17460614
- Tamburella et al (2010)
- The beta(3) adrenoceptor agonist, amibegron (SR58611A) counteracts stress-induced behavioral and neurochemical changes. Eur.Neuropsychopharmacol. 20 704 PMID: 20537869 [4]
- Wistar rats stressor procedures
- Increased the immobility time in the FST and reduced hippocampal BDNF and Bcl-2/Bax ratio proteins expression
- Counteracted by amibegron (5 and 10mg/kg) treatment
- Different results were obtained in animals treated with clomipramine or citalopram [9]
Solabegron
- Selective agonist for the ß3 adrenergic receptor
- Developed for the treatment of overactive bladder and irritable bowel syndrome.
- Acids, Carbocyclic [4]
- Investigated for use/treatment in diabetes mellitus type 2, irritable bowel syndrome (IBS), and urinary incontinence [3]
ZD 2079
- Beta 3-adrenoceptor agonist [4]
- Chemical Name: 4-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethoxy]-benzeneacetic acid hydrochloride
- Relaxes rat mesenteric artery and isolated aorta in vitro.
- Inhibits ob gene expression and circulating leptin levels in lean mice in vivo.
- Formula C18H21NO4.HCl
- Brawley et al (2000)
- Role of endothelium/nitric oxide in atypical beta-adrenoceptor-mediated relaxation in rat isolated aorta. Eur.J.Pharmacol. 398 285 PMID: 10854841
- Kozlowska et al (2003)
- Atypical beta-adrenoceptors, different from beta3-adrenoceptors, relax the rat isolated mesenteric artery. Br.J.Pharmacol. 140 3 PMID: 12967929
- Trayhurn et al (1996)
- Rapid inhibition of ob gene expression and circulating leptin levels in lean mice by the beta3-adrenoceptor agonists BRL 35135A and ZD2079. Biochem.Biophys.Res.Comm. 228 605 [4]
ZD 7114 hydrochloride
- Beta 3 agonist [4]
- Chemical Name: (S)-4-[2-Hydroxy-3-phenoxypropylaminoethoxy]-N-(2-methoxyethyl)phenoxyacetamide hydrochloride
- Formula C22H30N2O6.HCl
- Growcott et al (1993)
- Evaluation of ICI D7114, a putative stimulant of brown adipocytes, on histamine-contracted guinea-pig ileum. Br.J.Pharmacol. 109 1212 PMID: 8104647
- Savontaus et al (1998)
- Effects of ZD7114, a selective beta3-adrenoceptor agonist, on neuroendocrine mechanisms controlling energy balance. Eur.J.Pharmacol. 347 265 PMID: 9653893
- How (1993)
- Beta3-Adrenergic agonists. Drugs Future 18 529 [4]
