Beta3 -Adrenoceptor Agonists as Anti-diabetic and Anti-obesity Drugs in Humans

Abstract

In the early 1980s, an "atypical" beta-adrenergic receptor was discovered and subsequently called the beta (3)-adrenoceptor (beta(3)-AR). Agonists of the beta(3)-AR were observed to simultaneously increase lipolysis, fat oxidation, energy expenditure and insulin action leading to the belief that this receptor might serve as an attractive target for the treatment of diabetes and obesity. In vivo studies lent credence to this postulate with the finding that stimulation of this receptor by selective agonists lead to glycemic improvements and weight loss in rodent models of diabetes and obesity. This lead to intensive research efforts directed at developing beta(3)-AR selective agonists for the treatment of type 2 diabetes and obesity in humans. Unfortunately, endeavour been largely unsuccessful to date. Major obstacles have included the pharmacological differences between the rodent and human beta(3)-AR, the lack of selectivity of previous compounds for the beta(3)-AR over beta(1)-/beta(2)-ARs, and unsatisfactory oral bioavailability and pharmacokinetic properties. Cloning of the human beta(3)-AR has allowed for the development of novel compounds targeted specifically at the human receptor. Encouraging data has emerged from clinical studies wherein CL-316,243, a highly selective, albeit rodent specific beta(3)-AR agonist was observed to increase lipolysis, fat oxidation and insulin action in humans. More recently, beta(3)-AR agonists directed at the human receptor are showing promising results in their ability to increase energy expenditure in humans following a single dose. However, they do nor appear to be able to sustain their effects when administered chronically. Further clinical testing will be necessary, using compounds with improved oral bioavailability and potency, to help assess the physiology of the beta(3)-AR in humans and its attractiveness as a potential therapeutic for the treatment of type 2 diabetes and obesity.

Antagonists of GPR35 Display High Species Ortholog Selectivity and Varying Modes of Action

“…Observations of marked variation in the pharmacology of species orthologs of GPCRs are well known but are of particular relevance in the early stages of receptor characterization. For example, the differences in ligand affinity at the orthologs of the histamine H4 receptor (Liu et al, 2001) even led to suggestions that there might be other receptors for histamine and further detailed pharmacological characterization of various orthologs of this receptor (Lim et al, 2010;Schnell et al, 2011), and the development of early-generation ␤ 3 -adrenoceptor selective agonists was severely compromised by, at that time unappreciated, ortholog selectivity (de Souza and Burkey, 2001;Arch, 2008).…”

Therapeutic Targets: Progress of Their Exploration and Investigation of Their Characteristics

“…These agonists have been observed to simultaneously increase lipolysis, fat oxidation, energy expenditure and insulin action leading to the belief that this receptor might serve as an attractive target for the treatment of diabetes and obesity. However, drug design efforts have been hindered by the obstacles in the pharmacological differences between rodent and human ␤ 3 -AR, the lack of selectivity of leads, and unsatisfactory oral bioavailability and pharmacokinetic properties of tested agents (de Souza and Burkey, 2001). A recent test of ␤ 3 -AR agonists directed at the human receptor showed promising results in their ability to increase energy expenditure in humans after a single dose.…”

“…However, they do not seem to be able to sustain their effects when administered chronically. Further clinical testing will be necessary, using compounds with improved oral bioavailability and potency, to help assess the physiology of the ␤ 3 -AR in humans and its attractiveness as a potential therapeutic for the treatment of type 2 diabetes and obesity (de Souza and Burkey, 2001).…”

Synthesis and Evaluation of <i>N</i>-Phenyl-(2-aminothiazol-4-yl)acetamides with Phenoxypropanolamine Moiety as Selective β3-Adrenergic Receptor Agonists

“…Human clinical trials with these agents for use in treating metabolic disorders, however, have been disappointing due to a lack of efficacy or an unfavorable side-effect profile. 8,9) The clinical failure of such compounds has been attributed to a lack of sufficient β3-AR potency and selectivity relative to β1-and β2-ARs resulting from pharmacologic differences between rodent and human receptors, a notion supported by the discovery, cloning, and characterization of the human, rat, and mouse β3-ARs. [10][11][12] Recent studies have indicated that, in addition to adipocytes, the β3-AR is also distributed in human urinary bladder detrusor tissue and its relaxation occurs mainly via β3-AR.…”