Abstract
The role of β3- and other putative atypical β-adrenoceptors in human white adipocytes and right atrial appendage has been investigated using CGP 12177 and novel phenylethanolamine and aryloxypropanolamine β3-adrenoceptor (β3AR) agonists with varying intrinsic activities and selectivities for human cloned βAR subtypes. The ability to demonstrate β1/2AR antagonist-insensitive (β3 or other atypical βAR-mediated) responses to CGP 12177 was critically dependent on the albumin batch used to prepare and incubate the adipocytes. Four aryloxypropanolamine selective β3AR agonists (SB-226552, SB-229432, SB-236923, SB-246982) consistently elicited β1/2AR antagonist-insensitive lipolysis. However, a phenylethanolamine (SB-220646) that was a selective full β3AR agonist elicited full lipolytic and inotropic responses that were sensitive to β1/2AR antagonism, despite it having very low efficacies at cloned β1- and β2ARs. A component of the response to another phenylethanolamine selective β3AR agonist (SB-215691) was insensitive to β1/2AR antagonism in some experiments. Because novel aryloxypropanolamine had a β1/2AR antagonist-insensitive inotropic effect, these results establish more firmly that β3ARs mediate lipolysis in human white adipocytes, and suggest that putative ‘β4ARs‘ mediate inotropic responses to CGP 12177. The results also illustrate the difficulty of predicting from studies on cloned βARs which βARs will mediate responses to agonists in tissues that have a high number of β1- and β2ARs or a low number of β3ARs.
Footnotes
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Send reprint requests to: Dr. J. R. S. Arch, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK.
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↵1 Current address: University of Buckingham, Hunter Street, Buckingham, MK18 1EG, UK.
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↵2 Supported by the British Heart Foundation.
- Abbreviations:
- βAR
- β-adrenoceptor
- CHO
- Chinese hamster ovary
- MEM
- minimal essential medium
- CGP12177
- (±)-4-(3-t-butylamino-2-hydroxypropoxy)benzimidazol-2-one
- ICI 118551
- D-(±)-1-(7-methylylindan-4-yloxy)-3-isopropylaminobutan-2-ol
- CGP 20712A
- (±)-[2-(3-aminocarbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl)phenoxy]-2-propanol hydrochloride
- CL 316243
- disodium (RR) -5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,3-benzodioxazole-2,2-dicarboxylate
- BRL-37344
- (RR+SS)-(±)-4-[2-(2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl]phenoxyacetate
- SB-215691
- (RS+RR) 3-hydroxypropyl 4-[2-[2-(3,4-dihydroxyphenyl)-2-hydroxyethylamino]propyl]phenoxymethylphosphonate ethyl ester, dihydrate
- SB-220646
- (R, R)-5-{2-[2-(3,4-dihydroxyphenyl)-2-hydroxyethylamino]propyl}-1,3-benzodioxole-2,2-dicarboxylate
- SB-226552
- (S)-4-{2-[2-hydroxy-3-(4-hydroxyphenoxy)propylamino]ethyl}phenoxymethylcyclohexylphosphinic acid lithium salt
- SB-229432
- (SR)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propylamino]propyl}phenoxymethylphenylphosphinic acid, lithium salt
- SB-232602
- (S)-N-{2-hydroxy-5-[2-hydroxy-3-(4-methoxyphenyl)ethylamino]propoxy}methanesulfonamide hydrochloride
- SB-236923
- (SR) 4-{2-[2-(2-hydroxy-3-(4-hydroxy-3-methanesulfonylaminophenoxy)-propyl)amino]propyl}phenoxymethylphenylphosphinic acid, hydrobromide
- SB-246982
- (S)-2-(4-(2-(2-(3-(3-N-phenylsulfonylamino-4-hydroxyphenoxy)-hydroxypropyl)amino)ethyl)benzyloxy)benzoic acid, trifluoroacetate
- SB-248320
- (S)-diphenyl-4-{2-[2-hydroxy-3-(4-hydroxy-3-iso-propylsulfonyl-aminophenoxy)propylamino]ethyl}phenoxymethyl phosphine oxide
- Received October 13, 1997.
- Accepted February 6, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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