| Abstrakt: |
The in vitroactivity of four aryl propanolamines was compared to two prototypic β3receptor agonists, CGP 12177 and CL316243 at the human β3receptor, the rat β3receptor in the stomach fundus and receptors mediating atrial tachycardia.L‐739,574 was the most potent (EC50=9 nM) and selective agonist at the human β3receptor with high maximal response (74% of the maximal response to isoproterenol).A phenol‐biaryl ether analogue possessed modest affinity for the human β3receptor (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.These agonists at the human β3receptor did not activate the rat β3receptor in the rat stomach fundus. In fact, the aryl propanolamines (10−6M) inhibited CL316243‐induced activation of the rat β3receptor. Thus, agonist activity at the human β3receptor translated into antagonist activity at the rat β3receptor.L739,574 and the phenol biaryl ether increased heart rate viaβ1receptors.Although CGP12177 produced atrial tachycardia, neither the indole sulphonamide nor biphenyl biaryl ether did, although both had high affinity for the human β3receptor. Thus, the atrial tachycardic receptor was not identical to the human β3receptor.These studies (a) characterized four aryl propanolamines with high affinity at the human β3receptor, (b) found that they were antagonists at the rat β3receptor, an observation with profound implications for in vivorat data, and (c) established that the rodent atrial non‐β1, β2or β3tachycardic receptor was also unrelated to the human β3receptor. |
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