β3-Adrenoceptor agonists: potential, pitfalls and progress

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Abstract

β3-Adrenoceptor agonists are very effective thermogenic anti-obesity and insulin-sensitising agents in rodents. Their main sites of action are white and brown adipose tissue, and muscle. β3-Adrenoceptor mRNA levels are lower in human than in rodent adipose tissue, and adult humans have little brown adipose tissue. Nevertheless, β3-adrenoceptors are expressed in human white as well as brown adipose tissue and in skeletal muscle, and they play a role in the regulation of energy balance and glucose homeostasis. It is difficult to identify β3-adrenoceptor agonist drugs because the pharmacology of both β3- and β1-adrenoceptors can vary; near absolute selectivity is needed to avoid β1/2-adrenoceptor-mediated side effects and selective agonists tend to have poor oral bioavailability. All weight loss is lipid and lean may actually increase, so reducing weight loss relative to energy loss. β3-adrenoceptor agonists have a more rapid insulin-sensitising than anti-obesity effect, possibly because stimulation of lipid oxidation rapidly lowers intracellular long-chain fatty acyl CoA and diacylglycerol levels. This may deactivate those protein kinase C isoenzymes that inhibit insulin signalling.

Introduction

Although the β3-adrenoceptor was not cloned until 1989 (Emorine et al., 1989), it had already been apparent for 5 or 6 years that agonists of this receptor might have potential in the treatment of obesity and Type 2 diabetes Arch and Ainsworth, 1983, Arch et al., 1984a. Early evidence for the β3-adrenoceptor stemmed from the discovery that β1- and β2-adrenoceptor antagonists lacked potency in various gut preparations and as antagonists of β-adrenoceptor agonist-driven lipolysis. Then in the early 1980s, novel β-adrenoceptor agonists were discovered to be more potent as stimulants of rat white or brown adipocyte lipolysis than as stimulants of atrial contraction, or tracheal or uterine relaxation (Arch et al., 1984a). These compounds were found to stimulate metabolic rate and to have anti-obesity and anti-diabetic (insulin-sensitising) activity in rats and mice Arch et al., 1984b, Meier et al., 1984, Yen et al., 1984, Cawthorne et al., 1984.

Since that time, numerous studies have produced similar results in rodents for other β3-adrenoceptor agonists (e.g. Umekawa et al., 1997, Kiso et al., 1999); the β3-adrenoceptor and β3-adrenoceptor agonists have been reviewed regularly Arch and Kaumann, 1993, Arch, 2001, Dow, 1997, Weyer and de Souza, 2000, and there have been two books on the subject Goldberg and Frishman, 1995, Strosberg, 2000. No β3-adrenoceptor agonist has, however, advanced beyond Phase II clinical studies. In this brief review, I shall describe the status and discuss the potential of β3-adrenoceptor agonists for the treatment of obesity, touching also upon Type 2 diabetes. First though, I shall describe some of the problems of identifying β3-adrenoceptor agonists suitable for development as drugs.

Section snippets

Rodent vs. human receptors

The first generation β3-adrenoceptor agonists were identified largely from studies in vivo in rats and mice. These compounds were therefore optimised for selectivity at the rodent β3-adrenoceptor. When the human β3-adrenoceptor was cloned and expressed by Strosberg et al. (Emorine et al., 1989), one of the first generation compounds [(RR+SS)-(±)-4-[2-(2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl]phenoxyacetate (BRL-37344)] was shown to be a potent stimulant of cyclic AMP synthesis. It was

Role of the β3-adrenoceptor in man

The key sites of action for β3-adrenoceptor agonists appear to be skeletal muscle (Astrup et al., 1985), brown adipose tissue (Foster and Frydman, 1978) and (not as a site of thermogenesis but as a source of fuel) white adipose tissue Schiffelers et al., 1998, Havel et al., 1964. For a fuller discussion, see Arch (2001). β3-adrenoceptor mRNA is expressed in lower amounts in human than in rodent adipose tissue and the promoter for the human β3-adrenoceptor appears to drive expression of the mRNA

Status report

The attraction of β3-adrenoceptor agonists as potential drugs for the treatment of obesity and Type 2 diabetes is plain to see. The difficulties of producing a compound with good efficacy, selectivity and pharmacokinetic properties suitable for stimulation of the small numbers of β3-adrenoceptor present in man have, however, defeated a number of pharmaceutical companies. Recent interest has been evident from Merck, from where there have been a number of publications, but an abstract describing

Acknowledgments

I am grateful to Elliot Danforth Jr. and Terry Kenakin for the suggestions that have improved this manuscript, and to David G. Smith for the chemical advice. I would also like to thank Rosemary Wallis for the many manuscripts that she has prepared for me on β3-adrenoceptors and other topics during my time at SmithKline Beecham and GlaxoSmithKline.

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