Aryl propanolamines: comparison of activity at human β(3) receptors, rat β(3) receptors and rat atrial receptors mediating tachycardia

1. The in vitro activity of four aryl propanolamines was compared to two prototypic β(3) receptor agonists, CGP 12177 and CL316243 at the human β(3) receptor, the rat β(3) receptor in the stomach fundus and receptors mediating atrial tachycardia. 2. L-739,574 was the most potent (EC(50)=9 nM) and selective agonist at the human β(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 β(3) receptor (EC(50)=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 β(3) receptor did not activate the rat β(3) receptor in the rat stomach fundus. In fact, the aryl propanolamines (10(−6) M) inhibited CL316243-induced activation of the rat β(3) receptor. Thus, agonist activity at the human β(3) receptor translated into antagonist activity at the rat β(3) receptor. 5. L739,574 and the phenol biaryl ether increased heart rate via β(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 β(3) receptor. Thus, the atrial tachycardic receptor was not identical to the human β(3) receptor. 7. These studies (a) characterized four aryl propanolamines with high affinity at the human β(3) receptor, (b) found that they were antagonists at the rat β(3) receptor, an observation with profound implications for in vivo rat data, and (c) established that the rodent atrial non-β(1), β(2) or β(3) tachycardic receptor was also unrelated to the human β(3) receptor