Disease relevance of Brl 37344A

• Both isoproterenol and another beta 3AR-selective agonist, BRL 37344, increased RNA synthesis which was inhibited by pertussis toxin (PTX) [1].
• These results suggest that (1) the heat producing capacity of brown adipocytes is reduced by hypothalamic obesity and aging, and (2) BRL37344 might be useful as an anti-obesity drug [2].

High impact information on Brl 37344A

• The negative inotropic effects of a beta3-adrenoceptor agonist, BRL 37344, and also of norepinephrine in the presence of alpha- and beta1-2-blockade were inhibited both by a nonspecific blocker of NO, methylene blue, and two NO synthase (NOS) inhibitors, L-N-monomethyl-arginine and L-nitroarginine-methyl ester [3].
• Both dexamethasone and a beta3 agonist, BRL 37344, increased ZAG mRNA levels in 3T3-L1 adipocytes [4].
• After activation by a selective beta(3)-adrenergic receptor agonist, BRL 37344, there was a cGMP-dependent but NO-independent vasorelaxation that was selectively blocked by a specific beta(3)-receptor antagonist [5].
• This correlated with a lower potency of the beta 3-AR-selective agonists CGP12177, ICI201651, and BRL37344 in stimulating adenylate cyclase [6].
• BRL37344 stimulated proliferation, which could be blocked by inhibitors of Src, PI3K, and MEK [7].

Biological context of Brl 37344A

• This receptor expressed in Chinese hamster ovary (CHO) cells displays a low affinity for beta-adrenergic antagonists and a high affinity for BRL 37344, an agonist that selectively stimulates lipolysis in adipose tissue [8].
• The in vitro effects of BRL37344 on isolated myometrial contractions, in the presence and absence of the specific BK(Ca) channel blocker, iberiotoxin (IbTX), were investigated [9].
• In addition, BRL37344 increased whole-cell currents over a range of membrane potentials, and this effect was reversed by 100 nM IbTX [9].
• 1 micromol/l BRL37344 mildly prolonged action potentials in guinea pig ventricle (APD(90):+7.8%) CONCLUSIONS: We have demonstrated a functional coupling between the beta(3)-adrenoceptor and ion channel function in the mammalian heart [10].
• BRL 37344 and CGP 12177 were without any significant effect on heart rate but induced a rapid and dramatic hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)[11]

Anatomical context of Brl 37344A

• DESIGN: Single and whole-cell electrophysiological BK(Ca) channel recordings from freshly dispersed myocytes were obtained in the presence and absence of BRL37344, a specific beta3-adrenoreceptor agonist [9].
• Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels [12].
• BRL37344 (100 micromol/) did not alter current amplitudes of KvLQT1/minK expressed in CHO cells or in Xenopus oocytes, excluding a direct effect of BRL37344 on the channel [10].
• Biphasic effects of the beta-adrenoceptor agonist, BRL 37344, on glucose utilization in rat isolated skeletal muscle [13].
• Background and purpose:In cardiac muscle, BRL 37344, a selective beta(3)-adrenoceptor agonist, activates the Na(+),K(+)-pump via NO signalling [14].

Associations of Brl 37344A with other chemical compounds

• Similar negative inotropic effects also resulted from the action of beta3-adrenoceptor agonists with an order of potency: BRL 37344 > SR 58611 approximately CL 316243 > CGP 12177 [15].
• The rank order of potency of agonists in functional and binding studies was BRL37344 greater than IPR less than (-)-norepinephrine greater than (-)-epinephrine both in 3T3 adipocytes and CHO-beta 3 cells [16].
• Following butyrate treatment, EC50 values of beta 1- and beta 2-selective agonists, dobutamine and fenoterol, were decreased, whereas that of the beta 3-selective agonist BRL37344 was increased [17].
• In vitro isometric tension studies demonstrated that BRL37344 exerted a significant concentration-dependent relaxant effect on human myometrial tissue (P < 0.05), and preincubation of these strips with IbTX attenuated this effect on both spontaneous and oxytocin-induced contractions (44.44 and 57.84% at 10(-5) M, respectively) [9].
• In addition, BRL 37344 and propranolol, ligands that act as agonists in the stimulation of cyclase, act as antagonists for ERK activation [18].

Gene context of Brl 37344A

• The selective beta3-adrenoceptor agonist BRL-37344 failed to affect anti-IgE-induced histamine release from cultured mast cells [19].
• The ob gene mRNA half-life was 9.4 h and was decreased to 2.4 h by 1 nM BRL 37344, indicating that the inhibitory effect of the beta 3-agonist might be due to destabilization of ob gene mRNA [20].
• By contrast, BRL 37344 and CGP 12177 increased the expression of UCP2 and UCP3 in both wild type and beta(3)-AR KO mice, whereas they increased the expression of PGC-1 in wild type mice only [21].
• Atypical beta-AR and beta 3-AR had an affinity about 10-50 times higher for sodium-4-(2-[2-hydroxy-2-(3-chlorophenyl)ethylamino]propyl)phenoxyace tate sesquihydrate (BRL37344) than the beta 1-AR subtype [16].
• Administration of BRL37344 to mice reduced ApN mRNAs in both adipose regions, and ApN levels in plasma [22].

Analytical, diagnostic and therapeutic context of Brl 37344A

• Stereoisomers of BRL37344 ((R*,R*)-(+/-)-methyl-4-[2-[2-hydroxy-2 -(3-chlorophenyl)ethylamino]propyl]-phenoxyacetic acid), a beta 3-adrenoceptor agonist, were synthesized and separated with good resolution by derivatization with 1-anthroyl cyanide prior to chiral HPLC [23].
• This and the reduction in vascular tissue effects observed with BRL 37344 suggest that uterine beta(3)-adrenoreceptor modulation may provide a novel scientific approach to tocolysis with fewer vascular adverse effects [24].
• BRL 37344 increased cGMP levels in BRL 37344 group more than control group, but this increase is less significant than cAMP levels (P>0.05) [25].
• Effects of formoterol and BRL 37344 on cAMP and cGMP levels in isolated myometrial strips (n=6) were evaluated by radioimmunoassay kits [25].
• Intravenous injections of BRL37344 (1-10 micromol/kg) and clenbuterol (0.01-1 micromol/kg) dose-dependently reduced 2-deoxy-D-glucose-induced acid secretion, with BRL37344 about forty times less potent than clenbuterol [26].

References