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Vol. 290, Issue 2, 649-655, August 1999
3-Adrenergic Receptor
Antagonists
Department of Molecular Pharmacology/Immunology and Rheumatology,
and Department of Medicinal Chemistry (R.N., A.E.W.), Merck & Co.,
Rahway, New Jersey
Although the functional presence of 
3-adrenergic
receptors (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 3-AR ligands analogous to the
rodent-specific agonist BRL37344. Recently, we described a new class of
aryloxypropanolamine 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 3-AR
antagonists with high affinity for the human receptor. L-748,328 and
L-748,337 bind the human cloned 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
1-AR. Their selectivity for human 3-AR
versus 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
3-AR. Moreover, both L-748,328 and L-748,337 inhibit the
lipolytic response elicited by the 3-AR agonist
L-742,791 in isolated nonhuman primate adipocytes. The
aryloxypropanolamine benzenesulfonamide ligands illustrated here and
elsewhere demonstrate high-affinity human 3-AR binding.
In addition, we describe specific 3'-phenoxy substitutions that
transform these compounds from potent agonists into selective antagonists.
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