gives direct action to the β-adrenergic receptor. r4: either hydroxyl group or hydrogen group in this position gives direct action to the β-receptor. summarizing a few β2-adrenoceptor agonists and their structure activity shows how they act differently referred to potency, selectivity, affinity and duration of action (see table 1): table 1 structure of β2-agonists chemical structurenamedescription epinephrine (adrenalin)combination of catechol nucleus, β-hydroxyl group and n-methyl group. these idendities give direct action and a strong affinity for all adrenergic receptors. terbutalinecombination of n-t-butyl and a resorcinol phenyl ring that gives potency to the β2-receptor. albuterol (salbutamol)has n-t-butyl and a salicyl alcohol phenyl ring which gives it optimal β2-selectivity. salbutamol is a short-acting β2-agonist, but has a rapid onset of action. its onset by inhalation is within 5 minutes. the hydroxyl group on the β-carbon is a mixture of s- and r-isomers, where the r-isomer is the active one. another drug, levalbuterol, has exactly the same structure. it contains only the r-isomer of albutarol and is therefore much more active and the dose would be fourfold less for levalbuterol than albutarol. salmeterolhas a n-phenylbutoxyhexyl substituent, β-hydroxyl group and a salicyl phenyl ring that gives potency and direct selectivity for β2-receptor. the optimal position of the ether oxygen in the chain of salmeterol for both potency and duration is six carbon atoms from the basic nitrogen. formoterolhas an n-isopropyl-p-methoxyphenyl group that gives direct-action to β-receptors. formeterol also has a m-formamide and p—hydroxyphenyl ring, which gives selectivity to β2-receptors. formeterol’s onset of action is about 20 minutes, but duration of action of 12 hours. if formeterol is compared to salmeterol then it has greater water solubility that allows it to get to receptor sites faster and the lipophilicity keeps it in the lungs longer. formeterol has two asymmetric centers. the r,r-enantiomer is reported to be 1000 times more active then s,s-enantiomer. vilanterolthe latest drug on the market. it has similar structure to salmeterol but also 2,6 dichlorobenzyl and two alkoxy groups on the n-chain. it has demonstrated similar selectivity as salmeterol for β2-receptor but greater selectivity compared to all other agonists tested. the intrinsic activity was demonstrated to be greater than salmeterol. vilanterol is very potent and has a high potency. it has a fast onset of action and long duration of action. the inclusion of the extra alkoxy group on the side chain gives a potent β2-agonist that is rapidly metabolized in human liver. the 2,6-dichlorobenzyl seems to give greater potency, selectivity, rapid onset of action, long duration of action and rapid turnover. synthesis of β2-adrenoceptor agonists the β2-agonsist that are clinically used are all substituted β-phenethylamine (see figure 5) and they have three kinds of phenyl rings shown in figure 4. they are called resorcinol ring, salicyl alcohol ring or n-formamide ring. the alcohol substituents in the phenyl ring are reactive and complicate the synthesis of the β2-agonists. a protection step is needed while the n-residue is added in position r1 (figure 5). another thing that complicates the synthesis is obtaining optically pure r (-) enantiomer of the compound. the stereochemistry is very important for activity because only the r (-) enantiomer is able to form the hydrogen bonds necessary to fit in the binding site and activate the β2-receptor. salbutamol is usually inhaled in racemic mixtures (for example ventolin). by treating asthma with optically pure (r)-salbutamol the risk of side effects, such as nervous system stimulatory effects and cardiac arrythmia, can be minimized. there are several routes for enantioselective synthesis, as well as methods for synthesis of the racemic mixture followed by chiral resolution. stereoselective synthesis of tributalin and salbutamol acetal can be done from o-protected-(r)-cyanohydrins. f. effenberg, et al. describe a way for the synthesis. the main complications are to perform the deprotection step without racemization and to form a pure salt. a ritter reaction can be used for an n-tertiary butylation. in this experiment deacetylation of (r)-salbutamol acetal was unsuccessful so it can not be used to obtain pure (r)-salbutamol. figure 6 shows the main steps in the synthesis of salmeterol and tributalin. figure 6: synthesis of tributalin and salbutamol from cyanohydrins