Aryl propanolamines:: comparison of activity at human β3 receptors, rat β3 receptors and rat atrial receptors mediating tachycardia

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