Thermogenic and antiobesity activity of a novel β-adrenoceptor agonist (BRL 26830A) in mice and rats

Abstract

The effects of a novel compound, BRL 26830A, on energy balance in normal and obese mice have been investigated. BRL 26830A reduced body weight or weight gain in genetically (ob/ob), goldthioglucose, and cafeteria diet obese mice and genetically obese (fa/fa) Zucker rats. Weight reduction was due to reduced body lipid content. BRL 26830A caused little or no reduction in food intake in these animals but it increased metabolic rate and in genetically obese mice this thermic effect was increased by repeat dosing. BRL 26830A did not reduce body weight gain in the lean counterparts of the genetically obese animals. Its thermic effect was smaller in the lean than the genetically obese mice and it caused an increase in food intake in the lean mice. The thermic effect of BRL 26830A was inhibited by dl- but not d-propranolol. BRL 26830A largely overcame the depression in metabolic rate caused by fasting.

Development of ?3-adrenoceptor agonists as antiobesity and antidiabetes drugs in humans: Current status and future prospects

“…Chronic treatment of obese rodents with β 3 -AR agonists consistently produces a reduction in body weight [Arch and Ainsworth, 1983;Tan and Curtis-Prior, 1983;Arch et al, 1984a,b;Yen et al, 1984;Smith et al, 1985;Holloway et al, 1992;Largis et al, 1994;Yoshida et al, 1994a,b], which can be attributed almost entirely to a decrease in body fat stores [Arch and Wilson, 1996]. This reduction in adiposity is thought to be primarily caused by an increase in energy expenditure, i.e., a sustained stimulation of BAT-mediated thermogenesis, since average energy intake remains unaltered [Yoshida et al, 1994a;Ghorbani et al, 1998;Burkey et al, 2000].…”

“…It was not until the early 1980s that work by Arch and colleagues provided more solid pharmacological evidence for the existence of an atypical β-AR, called β 3 -AR [Arch and Ainsworth, 1983;Tan and Curtis-Prior, 1983;Arch et al, 1984a;Smith et al, 1985]. This group found that the lipolytic effects of a novel series of β-adrenergic agonists could not be blocked by classical β 1 -and β 2 -AR antagonists [Arch and Ainsworth, 1983;Tan and CurtisPrior, 1983;Arch et al, 1984a,b;Smith et al, 1985]. Later in that decade, the existence of this third member of the β-AR family was confirmed when the human and subsequently the rat β 3 -AR genes were cloned and sequenced [Emorine et al, 1989;Granneman et al, 1991Granneman et al, , 1993.…”

“…While the majority of previous and current antiobesity compounds are targeted at a reduction of energy intake (anorectic drugs), pharmacological approaches to increase energy expenditure (thermogenic drugs) are an alternative option for the treatment of obesity. The discovery of a third atypical β-adrenergic receptor, the β 3 -adrenoceptor (β 3 -AR), in the early 1980s [Tan and Curtis-Prior, 1983;Arch and Ainsworth, 1983;Arch et al, 1984a,b;Smith et al, 1985] and the finding that stimulation of this receptor by selective agonists led to marked weight loss in rodent models of obesity, mainly by increasing energy expenditure [Smith et al, 1985;Yen et al, 1984;Holloway et al, 1992;Largis et al, 1994;Yoshida et al, 1994a,b;Munro et al, 1987], raised hopes that these agents could be developed as thermogenic antiobesity drugs in humans [Howe, 1993;Arner, 1995;Lowell and Flier, 1995;Arch and Wilson, 1996; Himms-Hagen and Danforth, 1996;Danforth and Himms-Hagen, 1997;Weyer et al, 1999]. Moreover, in rodent models of Type 2 diabetes these agonists were found to exert potent antidiabetic effects, mainly by increasing insulin sensitivity [Smith et al, 1985;Largis et al, 1994;Yoshida et al, 1994a].…”

The role of brown adipose tissue in diet-induced thermogenesis

“…This is accompanied by a restoration of normal thermic responses to feeding, and levels of metabolic efficiency decrease to values similar to those of lean animals. Likewise, administration of P-adrenergic drugs that are highly selective agonists of BAT (Arch et al 1984) cause reductions in body-weight and fat, and increases in heat production in obese animals (Arch & Ainsworth, 1983). Thus, increases in BAT activity induced by cold, adrenalectomy and BAT-selective agonists result in an increased capacity for DIT and reductions in energetic efficiency.…”

In Silco Molecular Modeling of Chalcone Based Aryloxyethylamines as Antihyperglycemic Agents

“…β 3 -AR agonists were observed to concurrently augment lipolysis, fat oxidation, energy outlay [5] and insulin action foremost to the belief that, this receptor might afford as an attractive target for the treatment of diabetes and obesity [6]. Arylethanolamines and aryloxypropanolamines were first reported as β 3 -AR agonists earlier [7].…”