Potent and Selective Human β3-Adrenergic Receptor Antagonists

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 290; no. 2; p. 649
• Main Authors: Mari Rios Candelore, Liping Deng, Laurie Tota, Xiao-Ming Guan, Angela Amend, Yong Liu, Ron Newbold, Margaret A. Cascieri, Ann E. Weber
• Format: Journal Article
• Language: English
• Published: American Society for Pharmacology and Experimental Therapeutics 01.08.1999
• ISSN: 0022-3565; 1521-0103

Although the functional presence of β 3 -adrenergic receptors (β 3 -AR) in rodents is well established, its significance in human adipose tissue has been controversial. One of the issues confounding the experimental data has been the lack of potent and selective human β 3 -AR ligands analogous to the rodent-specific agonist BRL37344. Recently, we described a new class of aryloxypropanolamine β 3 -AR agonists that potently and selectively activate lipolysis in rhesus isolated adipocytes and stimulate the metabolic rate in rhesus monkeys in vivo. In this article, we describe novel and selective β 3 -AR antagonists with high affinity for the human receptor. L-748,328 and L-748,337 bind the human cloned β 3 -AR expressed in Chinese hamster ovary (CHO) cells with an affinity of 3.7 ± 1.4 and 4.0 ± 0.4 nM, respectively. They display an affinity of 467 ± 89 and 390 ± 154 nM for the human β 1 -AR. Their selectivity for human β 3 -AR versus β 2 -AR is greater than 20-fold (99 ± 43 nM) and 45-fold (204 ± 75 nM), respectively. These compounds are competitive antagonists capable of inhibiting the functional activation of agonists in a dose-dependent manner in cells expressing human cloned β 3 -AR. Moreover, both L-748,328 and L-748,337 inhibit the lipolytic response elicited by the β 3 -AR agonist L-742,791 in isolated nonhuman primate adipocytes. The aryloxypropanolamine benzenesulfonamide ligands illustrated here and elsewhere demonstrate high-affinity human β 3 -AR binding. In addition, we describe specific 3′-phenoxy substitutions that transform these compounds from potent agonists into selective antagonists.