Orally Bioavailable β3-Adrenergic Receptor Agonists as Potential Therapeutic Agents for Obesityand Type-II Diabetes

Hu, Baihua; Jennings, Lee L

doi:10.1016/s0079-6468(02)41005-3

Cited by 31 publications

(13 citation statements)

References 61 publications

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“…Activation of the sympathetic nervous system through ␤ -adrenergic receptors (ARs), in particular ␤ 3-AR (ADRB3), which is predominantly expressed in adipose tissue ( 25 ), is closely linked to the induction of thermogenic beige adipocytes (also known as brite, inducible brown, or brown-like adipocytes) in rodents and humans (26)(27)(28)(29). Cold exposure or ADRB3 agonists activate the classic lipolytic pathway through ARs to stimulate cAMP/protein kinase A (PKA) signaling, lipid mobilization, and browning in WAT ( 30 ).…”

Section: Body Composition and Analysis Of Energy Balancementioning

confidence: 99%

Berardinelli-Seip congenital lipodystrophy 2 regulates adipocyte lipolysis, browning, and energy balance in adult animals

Zhou

Lei

Benson

et al. 2015

Journal of Lipid Research

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Section: Body Composition and Analysis Of Energy Balancementioning

confidence: 99%

Berardinelli-Seip congenital lipodystrophy 2 regulates adipocyte lipolysis, browning, and energy balance in adult animals

Zhou

Lei

Benson

et al. 2015

Journal of Lipid Research

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“…These compounds have lower potency for human β3-ARs than for rodent receptors, and they act as only partial agonists in humans [14,18-20,22,42]. Subsequent recognition of important pharmacological differences between rodent and human β3-ARs has led to the development of novel β3-AR agonists that are potent and highly selective toward human β3-ARs [19,30,42,43]. …”

Section: Differences In β3-ar Between Rodents and Humansmentioning

confidence: 99%

Beta3-Adrenoceptor Agonists: Possible Role in the Treatment of Overactive Bladder

2010

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In the present review article, we present an overview of beta-adrenoceptor (β-AR) subtype expression at the mRNA and receptor protein levels in the human detrusor, the in vitro and in vivo bladder function of the β3-AR, the in vivo effect of β3-AR agonists on detrusor overactivity in animal models, and the available results of clinical trials of β3-AR agonists for treating overactive bladder (OAB). There is a predominant expression of β3-AR mRNA in human bladder, constituting 97% of total β-AR mRNA. Also, functionally, the relaxant response of human detrusor to catecholamines is mainly mediated through the β3-ARs. Moreover, the presence of β1-, β2-, and β3-AR mRNAs in the urothelium and suburothelial layer of human bladder has been identified. Stimulation of urothelial β-ARs results in the release of nitric oxide and an unknown substance inhibiting detrusor contractions from the urothelium. Intravenous application of CL316,243, a selective β3-AR agonist, in rats selectively inhibits mechano-sensitive Aδ-fiber activity of the primary bladder afferents. A number of selective β3-AR agonists are currently being evaluated in clinical trials for OAB with promising preliminary results. In conclusion, the β3-AR agonists are the most notable alternative class of agents to antimuscarinics in the pharmacological treatment of OAB. The β3-AR agonists act to facilitate bladder storage function probably through at least two mechanisms: first, direct inhibition of the detrusor, and second, inhibition of bladder afferent neurotransduction.

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“…Subsequent recognition of important pharmacological differences between rodent and human ␤ 3 -ARs has led to the development of novel ␤ 3 -AR agonists that are potent and highly selective toward human ␤ 3 -ARs (Hu and Jennings, 2003).…”

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confidence: 99%

Effect of (R)-2-(2-Aminothiazol-4-yl)-4′-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} Acetanilide (YM178), a Novel Selective β₃-Adrenoceptor Agonist, on Bladder Function

Takasu¹,

Ukai²,

Sato³

et al. 2007

J Pharmacol Exp Ther

298

209

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We evaluated the pharmacological characteristics of (R)-2-(2-aminothiazol-4-yl)-4Ј-{2-[(2-hydroxy-2-phenylethyl)amino]-ethyl} acetanilide (YM178). YM178 increased cyclic AMP accumulation in Chinese hamster ovary (CHO) cells expressing human ␤ 3 -adrenoceptor (AR). The half-maximal effective concentration (EC 50 ) value was 22.4 nM. EC 50 values of YM178 for human ␤ 1 -and ␤ 2 -ARs were 10,000 nM or more, respectively. The ratio of intrinsic activities of YM178 versus maximal response induced by isoproterenol (nonselective ␤-AR agonist) was 0.8 for human ␤ 3 -ARs, 0.1 for human ␤ 1 -ARs, and 0.1 for human ␤ 2 -ARs. The relaxant effects of YM178 were evaluated in rats and humans bladder strips precontracted with carbachol (CCh) and compared with those of isoproterenol and 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (CGP-12177A) (␤ 3 -AR agonist). EC 50 values of YM178 and isoproterenol in rat bladder strips precontracted with 10 Ϫ6 M CCh were 5.1 and 1.4 M, respectively, whereas those in human bladder strips precontracted with 10 Ϫ7 M CCh were 0.78 and 0.28 M, respectively. In in vivo study, YM178 at a dose of 3 mg/kg i.v. decreased the frequency of rhythmic bladder contraction induced by intravesical filling with saline without suppressing its amplitude in anesthetized rats. These findings suggest the suitability of YM178 as a therapeutic drug for the treatment of symptoms of overactive bladder such as urinary frequency, urgency, and urge incontinence.

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Orally Bioavailable β3-Adrenergic Receptor Agonists as Potential Therapeutic Agents for Obesityand Type-II Diabetes

Cited by 31 publications

References 61 publications

Berardinelli-Seip congenital lipodystrophy 2 regulates adipocyte lipolysis, browning, and energy balance in adult animals

Berardinelli-Seip congenital lipodystrophy 2 regulates adipocyte lipolysis, browning, and energy balance in adult animals

Beta3-Adrenoceptor Agonists: Possible Role in the Treatment of Overactive Bladder

Effect of (R)-2-(2-Aminothiazol-4-yl)-4′-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} Acetanilide (YM178), a Novel Selective β₃-Adrenoceptor Agonist, on Bladder Function

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Orally Bioavailable β3-Adrenergic Receptor Agonists as Potential Therapeutic Agents for Obesityand Type-II Diabetes

Cited by 31 publications

References 61 publications

Berardinelli-Seip congenital lipodystrophy 2 regulates adipocyte lipolysis, browning, and energy balance in adult animals

Berardinelli-Seip congenital lipodystrophy 2 regulates adipocyte lipolysis, browning, and energy balance in adult animals

Beta3-Adrenoceptor Agonists: Possible Role in the Treatment of Overactive Bladder

Effect of (R)-2-(2-Aminothiazol-4-yl)-4′-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} Acetanilide (YM178), a Novel Selective β3-Adrenoceptor Agonist, on Bladder Function

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Effect of (R)-2-(2-Aminothiazol-4-yl)-4′-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} Acetanilide (YM178), a Novel Selective β₃-Adrenoceptor Agonist, on Bladder Function