1. The in vitro activity of four aryl
propanolamines was compared to two prototypic beta3 receptor agonists,
CGP 12177 and
CL316243 at the human beta3 receptor, the rat beta3 receptor in the stomach fundus and receptors mediating atrial
tachycardia. 2. L-739,574 was the most potent (EC50 = 9 nM) and selective agonist at the human beta3 receptor with high maximal response (74% of the maximal response to
isoproterenol). 3. A
phenol-biaryl
ether analogue possessed modest affinity for the human beta3 receptor (EC50 = 246 nM), but was highly efficacious with a maximal response 82% of the maximal response to
isoproterenol. The other derivatives were intermediate in potency with low maximal responses. 4. These agonists at the human beta3 receptor did not activate the rat beta3 receptor in the rat stomach fundus. In fact, the aryl
propanolamines (10(-6) M) inhibited CL316243-induced activation of the rat beta3 receptor. Thus, agonist activity at the human beta3 receptor translated into antagonist activity at the rat beta3 receptor. 5. L739,574 and the
phenol biaryl
ether increased heart rate via beta1 receptors. 6. Although CGP12177 produced atrial
tachycardia, neither the
indole sulphonamide nor
biphenyl biaryl
ether did, although both had high affinity for the human beta3 receptor. Thus, the atrial tachycardic receptor was not identical to the human beta3 receptor. 7. These studies (a) characterized four aryl
propanolamines with high affinity at the human beta3 receptor, (b) found that they were antagonists at the rat beta3 receptor, an observation with profound implications for in vivo rat data, and (c) established that the rodent atrial non-beta1, beta2 or beta3 tachycardic receptor was also unrelated to the human beta3 receptor.