Abstract
Although many beta1-receptor antagonists and beta2-receptor agonists
have been used in pharmacotherapy for many years their pharmacological
properties at all three known subtypes of beta-adrenergic receptors
are not always well characterized. The aim of this study was, therefore,
to provide comparative binding characteristics of agonists (epinephrine,
norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol,
terbutalin, formoterol, broxaterol) and antagonists (propranolol,
alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol,
BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three
subtypes of human beta-adrenergic receptors in an identical cellular
background. We generated Chinese hamster ovary (CHO) cells stably
expressing the three beta-adrenergic receptor subtypes at comparable
levels. We characterized these receptor subtypes and analyzed the
affinity of routinely used drugs as well as experimental compounds
in competition binding studies, using the non-selective antagonist
125I-cyanopindolol as a radioligand. Furthermore, we analyzed the
beta-receptor-mediated adenylyl cyclase activity in isolated membranes
from these cell lines. The results from our experiments show that
all compounds exhibit distinct patterns of selectivity and activity
at the three beta-receptor subtypes. In particular, a number of beta2-
or beta3-receptor agonists that are inverse agonists at the other
subtypes were identified. In addition, beta1-receptor antagonists
with agonistic activity at beta2- and beta3-receptors were found.
These specific mixtures of agonism, antagonism, and inverse agonism
at different subtypes may have important implications for the therapeutic
use of the respective compounds.
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