ICI D7114 a novel selective beta-adrenoceptor agonist selectively stimulates brown fat and increases whole-body oxygen consumption.
1. ICI D7114 is a novel, beta-adrenoceptor agonist which stimulates whole body oxygen consumption in conscious rats, cats and dogs and brown adipose tissue (BAT) activity in conscious rats. Treatment of rats with ICI D7114 stimulated oxygen consumption (ED50, 0.04 mg kg-1, p.o.) and BAT mitochondrial guanosine diphosphate (GDP)-binding (ED50, 0.15 mg kg-1, p.o.) with no chronotropic effects on the heart at these doses. 2. Reference beta-adrenoceptor agonists, isoprenaline and clenbuterol, also stimulated oxygen consumption and BAT activity but were less selective because they also produced effects on heart rate at these doses. 3. Treatment of conscious rats with ICI D7114 did not attenuate the chronotropic effects on the heart of a subsequent isoprenaline challenge. 4. Administration of ICI D7114 or of its acid metabolite had no effect in a cat soleus muscle model of tremor or on blood potassium levels in the conscious dog, indicating lack of effects at beta 2-adrenoceptors. 5. The results indicate that ICI D7114 may have activity at atypical beta-adrenoceptors in brown adipose tissue leading to increased whole body oxygen consumption.
Holloway
B R
BR
ICI Pharmaceuticals, Macclesfield, Cheshire.
Howe
R
R
Rao
B S
BS
Stribling
D
D
Mayers
R M
RM
Briscoe
M G
MG
Jackson
J M
JM
D002001:Adipose Tissue, Brown / Q000187:drug effects*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects; D002415:Cats; D002976:Clenbuterol / Q000494:pharmacology; D004285:Dogs; D004837:Epinephrine / Q000494:pharmacology; D006153:Guanosine Diphosphate / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D010642:Phenoxyacetates / Q000494:pharmacology*; D050198:Phenoxypropanolamines; D011188:Potassium / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D013268:Stimulation, Chemical
D000318:Adrenergic beta-Agonists; D010642:Phenoxyacetates; D050198:Phenoxypropanolamines; C071909:ICI D7114; D006153:Guanosine Diphosphate; D007545:Isoproterenol; D011188:Potassium; D002976:Clenbuterol; D004837:Epinephrine