ICI D7114 a novel selective β‐adrenoceptor agonist selectively stimulates brown fat and increases whole‐body oxygen consumption

Abstract

1 ICI D7114 is a novel, fi-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, 0.04mgkg-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 fl-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 /12-adrenoceptors. 5The results indicate that ICI D7114 may have activity at atypical fi-adrenoceptors in brown adipose tissue leading to increased whole body oxygen consumption.

Anti-Obesity Effects of Selective Agonists to the .BETA.3-Adrenergic Receptor in Dogs. I. The Presence of Canine .BETA.3-Adrenergic Receptor and in vivo Lipomobilization by Its Agonists.

“…Various compounds having agonistic activity to β3-AR have been developed, mainly using isolated adipocytes and Chinese hamster ovary cells transfected with mouse β3-ARs [2,4,11]. In the present study, we used two agonists, CL316,243 and ICI D7114, both of which were confirmed to be selective agonists of rodent β3-ARs [2,11].…”

“…In the present study, we used two agonists, CL316,243 and ICI D7114, both of which were confirmed to be selective agonists of rodent β3-ARs [2,11]. ICI D7114 is an aryloxypropanolamine compound, while CL316,243 is a phenylethanolamine (Fig.…”

“…Another β3-AR agonist, ICI D7114 (its acid metabolite), [(S)-4-(2-hydroxy-3-phenoxypropylaminoethoxy)-N-(2-methoxyethyl)phenoxyacetamide] [11], was In mammals, there are two types of adipose tissues, white and brown adipose tissues. Although both tissues consist of a large number of adipocytes accumulating triglycerides, their physiological roles contrast: that is, white adipose tissue is the major site of energy storage and releases fatty acids into blood, while brown adipose tissue oxidizes fatty acids to produce heat and is the site of energy expenditure.…”

Effects of the two β3-agonists, ZD7114 and ZD2079 on 24 hour energy expenditure and respiratory quotient in obese subjects

“…With the unselective b-agonist isoprenaline a marked increase in heart rate is observed in rats at the ED 50 dose for its thermogenic effect. 6 This demonstrates the selectivity of the ZD7114's b-activity in rats to increase EE. Furthermore, b 3 -agonistic capacity of ZD7114 has previously been demonstrated in rats by an increased mitochondrial guanosine diphosphate (GDP) binding in brown adipocytes which represents a marker of b 3 -stimulation.…”

“…11 These results are in contrast to the marked acute thermogenic effect of the compound both in dogs and rats at a dose of 0.1 mgakg body weight. 6 The ED 50 dose for the thermogenic effect of ZD7114 in rats was 0.04 mgakg body weight whereas 1.0 mgakg was required to achieve a detectable increase in heart rate. With the unselective b-agonist isoprenaline a marked increase in heart rate is observed in rats at the ED 50 dose for its thermogenic effect.…”