The difference between substituents R1-R5 is described below. All marketed β-agonists have hydroxyl group in position R3 and most often in position R5.
R: This group determines α- or β-receptor selectivity. The larger the substituent, the greater the selectivity for the β-receptor. If t-butyl is positioned at R it shows high affinity for the β-receptor. A long phenylbutoxyhexyl substituent in this position gives high β-selectivity and also high lipophilicity and therefore a longer duration of action.
R: Substituents other than hydrogen would give increased duration of action. An ethyl group would increase the selectivity for the β-receptor. However, an ethyl group seems to cause increased adverse effects and low β-receptor potency compared to other β-selective agonists.
R: A hydroxyl group gives direct action to the β-receptor. As noted earlier, all marketed β-agonists have a hydroxyl group in this position which makes the compound chiral, and is active when it has the (R)-configuration.
R or R: Hydroxyl group placed on carbon number 5 or 3 (meta position) gives direct action to the β-adrenergic receptor.
R: Either hydroxyl group or hydrogen group in this position gives direct action to the β-receptor.
Summarizing a few β-adrenoceptor agonists and their structure activity shows how they act differently referred to potency, selectivity, affinity and duration of action (see table 1):