Aryl propanolamines: comparison of activity at human beta3 receptors, rat beta3 receptors and rat atrial receptors mediating tachycardia.
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.
Cohen
M L
ML
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
Bloomquist
W
W
Kriauciunas
A
A
Shuker
A
A
Calligaro
D
D
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D016275:Atrial Function; D004149:Dioxoles / Q000494:pharmacology; D006801:Humans; D008297:Male; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology; D022702:Receptors, Adrenergic, beta-3; D013610:Tachycardia / Q000209:etiology*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004149:Dioxoles; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; C033394:CGP 12177