Discovery of L-755,507: A subnanomolar human β3 adrenergic receptor agonist

Parmee, Emma R.; Ok, Hyun; Candelore, Mari R.; Tota, Laurie; Deng, Liping; Strader, Catherine D.; Wyvratt, Matthew J.; Fisher, Michael H.; Weber, Ann E.

doi:10.1016/s0960-894x(98)00170-x

Cited by 44 publications

(26 citation statements)

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“…Subsequently, the cloned human ␤ 3 -AR has been used to identify agonists with increased efficacy at the human ␤ 3 -AR and less efficacy at ␤ 1 -and ␤ 2 -ARs. One such agonist that has been identified is L755507 (37), which increased lipolysis and metabolic rate in rhesus monkey (17). Although these new human ␤ 3 -AR agonists may have a positive effect in human brown adipocytes, there is also the possibility that a different signaling pathway exists in human BAT.…”

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confidence: 99%

β₁-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β₃-adrenergic receptor-knockout mice via nonshivering thermogenesis

Mattsson

Csikasz

Chernogubova

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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With the finding that brown adipose tissue is present and negatively correlated to obesity in adult man, finding the mechanism(s) of how to activate brown adipose tissue in humans could be important in combating obesity, type 2 diabetes, and their complications. In mice, the main regulator of nonshivering thermogenesis in brown adipose tissue is norepinephrine acting predominantly via β3-adrenergic receptors. However, vast majorities of β3-adrenergic agonists have so far not been able to stimulate human β3-adrenergic receptors or brown adipose tissue activity, and it was postulated that human brown adipose tissue could be regulated instead by β1-adrenergic receptors. Therefore, we have investigated the signaling pathways, specifically pathways to nonshivering thermogenesis, in mice lacking β3-adrenergic receptors. Wild-type and β3-knockout mice were either exposed to acute cold (up to 12 h) or acclimated for 7 wk to cold, and parameters related to metabolism and brown adipose tissue function were investigated. β3-knockout mice were able to survive both acute and prolonged cold exposure due to activation of β1-adrenergic receptors. Thus, in the absence of β3-adrenergic receptors, β1-adrenergic receptors are effectively able to signal via cAMP to elicit cAMP-mediated responses and to recruit and activate brown adipose tissue. In addition, we found that in human multipotent adipose-derived stem cells differentiated into functional brown adipocytes, activation of either β1-adrenergic receptors or β3-adrenergic receptors was able to increase UCP1 mRNA and protein levels. Thus, in humans, β1-adrenergic receptors could play an important role in regulating nonshivering thermogenesis.

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confidence: 99%

β₁-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β₃-adrenergic receptor-knockout mice via nonshivering thermogenesis

Mattsson

Csikasz

Chernogubova

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…L748337 is a selective ␤ 3 -AR antagonist that competitively blocks cAMP responses to agonists in CHOh␤ 3 cells and inhibits lipolytic responses in primate adipocytes (Candelore et al, 1999). L755507 is a potent agonist at the human ␤ 3 -AR, with 440-fold selectivity for ␤ 3 -AR compared with ␤ 1 or ␤ 2 -ARs (Parmee et al, 1998). It elevates at ASPET Journals on May 9, 2018 molpharm.aspetjournals.org cAMP in CHOh␤ 3 cells, causes thermogenesis in transgenic mice expressing human ␤ 3 -ARs (Hu et al, 2001), and induces lipolysis and an elevation of metabolic rate in rhesus monkeys .…”

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The β₃-Adrenoceptor Agonist 4-[[(Hexylamino)carbonyl]amino]-N-[4-[2-[[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]-phenyl]-benzenesulfonamide (L755507) and Antagonist (S)-N-[4-[2-[[3-[3-(Acetamidomethyl)phenoxy]-2-hydroxypropyl]amino]-ethyl]phenyl]benzenesulfonamide (L748337) Activate Different Signaling Pathways in Chinese Hamster Ovary-K1 Cells Stably Expressing the Human β₃-Adrenoceptor

Sato

Hutchinson²,

Evans³

et al. 2008

Mol Pharmacol

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This study identifies signaling pathways activated by the ␤ 2 -/␤ 3 -adrenoceptor (AR) agonist zinterol, the selective ␤ 3 -AR agonist L755507, and the selective ␤ 3 -AR antagonist L748337 in CHO-K1 cells expressing human ␤ 3 -adrenoceptors. Zinterol and L755507 caused a robust concentration-dependent increase in cAMP accumulation (pEC 50 values of 8.5 and 12.3, respectively), whereas L748337 had low efficacy. Maximal cAMP accumulation with zinterol and L755507 was increased after pretreatment with pertussis toxin, indicating that the human ␤ 3 -AR couples to G i and to G s . In contrast to cAMP, zinterol, L755507 and L748337 increased phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2) with very high potency (pEC 50 values of 10.9, 11.7, and 11.6). These compounds also stimulated phosphorylation of p38 mitogen-activated protein kinase (MAPK) but with much lower potency than Erk1/2 (pEC 50 values of 5.9, 5.5, and 5.7, respectively). Pertussis toxin completely blocked Erk1/2 and p38 MAPK phosphorylation in response to L748337, demonstrating a requirement for G i/o coupling, whereas L755507-stimulated p38 MAPK phosphorylation was not inhibited by pertussis toxin, and Erk1/2 phosphorylation was inhibited by only 30%. We found that high levels of cAMP interfered with agonist-activated p38 MAPK phosphorylation. L748337 increased extracellular acidification rate (ECAR) in the cytosensor microphysiometer with efficacy similar to zinterol and L755507, albeit with lower potency (pEC 50 value of 7.2 compared with zinterol, 8.1, and L755507, 8.6). The ECAR response to L748337 was largely via activation of p38 MAPK, demonstrated by 65% inhibition with 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-3-butyn-1-ol (RWJ67657). We conclude that the ␤ 3 -AR agonist L755507 couples to both G s and G i to activate adenylate cyclase and MAPK signaling, whereas the ␤ 3 -AR antagonist L748337 couples predominantly to G i to activate MAPK signaling.␤-Adrenoceptors (ARs) mediate responses to circulating adrenaline and to noradrenaline released from sympathetic nerve terminals. The ␤ 1 -, ␤ 2 -, and ␤ 3 -AR subtypes have distinct patterns of expression in heart, lung, blood vessels, the gastrointestinal tract, adipose tissue, and the central ner-

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“…Thus, the benzenesulfonamide moiety represents a group of choice to prepare potent and selective agonists of the human b 3 -adrenoceptor. [18,19] Studies with compounds containing the benzenesulfonamide moiety with various substituents led to the preparation of L-755,507 (Figure 1), [19] which displays an excellent activity profile as an extremely potent and selective human b 3 -AR agonist. Unfortunately, it was found to have extremely poor oral bioavailability (< 1 % in dogs), presumably due to the polar and highly solvated urea moiety.…”

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confidence: 99%

The Tertiary Amine Nitrogen Atom of Piperazine Sulfonamides as a Novel Determinant of Potent and Selective β₃‐Adrenoceptor Agonists

et al. 2009

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Novel compounds were prepared in fair to good yields as human beta(3)-adrenoceptor (beta(3)-AR) agonists. In particular, aryloxypropanolamines 7 a-d (EC(50)=0.57-2.1 nM) and arylethanolamines 12 a,b,e (EC(50)=6.38-19.4 nM) were designed to explore the effects of modifications at the right-hand side of these molecules on their activity as beta(3)-AR agonists. Piperidine sulfonamides 15 a-c, e-g (EC(50)=6.1-36.2 nM) and piperazine sulfonamide derivatives 20-29 (EC(50)=1.79-49.3 nM) were examined as compounds bearing a non-aromatic linker on the right- and left-hand sides of the molecules. Some piperazine sulfonamides were found to be potent and selective beta(3)-AR agonists, even if the amine nitrogen atom is tertiary and not secondary, as is the case for all beta(3)-AR agonists reported so far. (S)-3-{4-{N-{4-{2-[2-Hydroxy-3-(4-hydroxyphenoxy)propylamino]ethyl}phenyl}sulfamoyl}phenoxy}propanoic acid (7 d; EC(50)=0.57 nM), (R)-N-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenyl}-4-(3-octylureido)benzenesulfonamide (12 e; EC(50)=6.38 nM), (R)-2-[1-(4-methoxyphenylsulfonyl)piperidin-4-ylamino]-1-phenylethanol (15 f; EC(50)=6.1 nM), and (S)-4-{2-hydroxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl]propoxy}phenol (25; EC(50)=1.79 nM) were found to be the most potent beta(3)-AR agonists of the aryloxypropanolamine, arylethanolamine, piperidine sulfonamide, and piperazine sulfonamide classes, respectively. The two most potent compounds were identified as possible candidates for further development of beta(3)-AR agonists useful in the treatment of beta(3)-AR-mediated pathological conditions.

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Discovery of L-755,507: A subnanomolar human β3 adrenergic receptor agonist

Cited by 44 publications

References 1 publication

β₁-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β₃-adrenergic receptor-knockout mice via nonshivering thermogenesis

β₁-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β₃-adrenergic receptor-knockout mice via nonshivering thermogenesis

The Tertiary Amine Nitrogen Atom of Piperazine Sulfonamides as a Novel Determinant of Potent and Selective β₃‐Adrenoceptor Agonists

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Discovery of L-755,507: A subnanomolar human β3 adrenergic receptor agonist

Cited by 44 publications

References 1 publication

β1-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β3-adrenergic receptor-knockout mice via nonshivering thermogenesis

β1-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β3-adrenergic receptor-knockout mice via nonshivering thermogenesis

The Tertiary Amine Nitrogen Atom of Piperazine Sulfonamides as a Novel Determinant of Potent and Selective β3‐Adrenoceptor Agonists

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β₁-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β₃-adrenergic receptor-knockout mice via nonshivering thermogenesis

β₁-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β₃-adrenergic receptor-knockout mice via nonshivering thermogenesis

The Tertiary Amine Nitrogen Atom of Piperazine Sulfonamides as a Novel Determinant of Potent and Selective β₃‐Adrenoceptor Agonists