RT Journal Article SR Electronic T1 Potent and Selective Human β3-Adrenergic Receptor Antagonists JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 649 OP 655 VO 290 IS 2 A1 Mari Rios Candelore A1 Liping Deng A1 Laurie Tota A1 Xiao-Ming Guan A1 Angela Amend A1 Yong Liu A1 Ron Newbold A1 Margaret A. Cascieri A1 Ann E. Weber YR 1999 UL http://jpet.aspetjournals.org/content/290/2/649.abstract AB Although the functional presence of β3-adrenergic receptors (β3-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 β3-AR ligands analogous to the rodent-specific agonist BRL37344. Recently, we described a new class of aryloxypropanolamine β3-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 β3-AR antagonists with high affinity for the human receptor. L-748,328 and L-748,337 bind the human cloned β3-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 β1-AR. Their selectivity for human β3-AR versus β2-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 β3-AR. Moreover, both L-748,328 and L-748,337 inhibit the lipolytic response elicited by the β3-AR agonist L-742,791 in isolated nonhuman primate adipocytes. The aryloxypropanolamine benzenesulfonamide ligands illustrated here and elsewhere demonstrate high-affinity human β3-AR binding. In addition, we describe specific 3′-phenoxy substitutions that transform these compounds from potent agonists into selective antagonists. The American Society for Pharmacology and Experimental Therapeutics