Potent and selective human beta(3)-adrenergic receptor antagonists

Although the functional presence of beta(3)-adrenergic receptors (beta(3)-A R) in rodents is well established, its significance in human adipose tissue has been controversial. One of the issues confounding the experimental dat a has been the lack of potent and selective human beta(3)-AR ligands analog ous to the rodent-specific agonist BRL37344. Recently, we described a new c lass of aryloxypropanolamine beta(3)-AR agonists that potently and selectiv ely activate lipolysis in rhesus isolated adipocytes and stimulate the meta bolic rate in rhesus monkeys in vivo. In this article, we describe novel an d selective beta(3)-AR antagonists with high affinity for the human recepto r. L-748,328 and L-748,337 bind the human cloned beta(3)-AR expressed in Ch inese 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 +/- 1 54 nM for the human beta(1)-AR. Their selectivity for human beta(3)-AR vers us beta(2)-AR is greater than 20-fold (99 +/- 43 nM) and 45-fold (204 +/- 7 5 nM), respectively. These compounds are competitive antagonists capable of inhibiting the functional activation of agonists in a dose-dependent manne r in cells expressing human cloned beta(3)-AR. Moreover, both L-748,328 and L-748,337 inhibit the lipolytic response elicited by the beta(3)-AR agonis t L-742,791 in isolated nonhuman primate adipocytes. The aryloxypropanolami ne benzenesulfonamide ligands illustrated here and elsewhere demonstrate hi gh-affinity human beta(3)-AR binding. In addition, we describe specific 3'- phenoxy substitutions that transform these compounds from potent agonists i nto selective antagonists.