Chemical Structure of Beta-Agonists

Nonselective, short-acting adrenergic agents and longer-acting, more selective beta2-agonists are
similar in structure in that they all possess a benzene ring. Greater selectivity has been achieved
by increasing the bulk of the alpha-carbon side chain.

To attain resistance to the rapidly deactivating properties of the enzyme catechol-O-

methyltransferase, modifications have been made to prolong activity, either by repositioning the
3,4-hydroxyl group on the benzene ring to the 3,5 position (metaproterenol, terbutaline, fenoterol)
or by substituting a 3-hydroxymethyl group (albuterol, pirbuterol, salmeterol) or a foramino group
(formoterol) for the 3-hydroxyl group. Although rapid-acting albuterol, pirbuterol, and terbutaline
have a high degree of beta2-agonist specificity, their hydrophilicity results in a short receptor
occupancy time, limiting their duration of action.

Recently, 2 new agents, formoterol and salmeterol, were developed, which, because of their highly
lipophilic properties, demonstrate activity for up to 24 hours. Salmeterol, which has a slow onset of
action, has an extended side chain that binds to a site in close proximity with the beta-receptor
called an exo-site. This binding allows the active saligenin head of the molecule to repeatedly
stimulate the G protein coupled receptor connected to adenylyl cyclase, thus accounting for its
prolonged activity. Formoterol's lipophilicity, although slightly less than that of salmeterol, allows it
to enter the plasma membrane in the form of a depot, from whence it is gradually released into the
aqueous phase to react with the beta-receptor, resulting in an extended duration of action. The
aqueous phase activity, not demonstrated by salmeterol, provides formoterol with a rapid onset of
action similar to that of albuterol.

and formoterol are two highly selective 2-agonists with a bronchodilating effect
lasting for at least 12 h after a single inhalation (1, 2). The molecular structure of both
long-acting inhaled 2-agonists (LABA) is, however, different (Figure 1). Salmeterol
is the result of a specific research program designed to achieve prolonged duration of
action by molecular modification of the short-acting 2-agonists salbutamol. The
resulting 25 Å molecule consists of the saligenin head of salbutamol that binds to the
active site of the 2-adrenergic receptor ( 2AR), coupled to a long aliphatic side chain
that profoundly increases the lipophilicity of the molecule. The concept has been
proposed that the molecule diffuses laterally through the cell membrane to approach
the 2AR. The side chain then interacts with an auxiliary binding site (exo-site), a
group of highly hydrophobic amino acids within the fourth domain of the 2AR.
Binding to the exo-site prevents dissociation of salmeterol from the 2AR and allows
the active saligenin head to repeatedly engage the active site of the receptor. This
mechanism would account for the long duration of the effect but slow onset of action
of salmeterol (3).

Figure 1. Mode of action of 2-agonists based

on the plasmalemma diffusion microkinetic
theory (taken with permission from reference 4).

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Formoterol, a formanilide substituted phenoethanolamine, was serendipitously found

to be long-acting when given by inhalation. The length of the side chain and resulting
lipophilicity of formoterol is intermediate between salmeterol and salbutamol. The
plasmalemma diffusion microkinetic theory predicts that the moderate lipophilicity of
formoterol allows it to enter the plasmalemma and to be retained. From this depot, the
molecule diffuses slowly to activate the 2AR over a prolonged period. Conversely,
sufficient drug remains available in the aqueous biophase to allow immediate
interaction with the active site of the receptor, accounting for its rapid onset of action.
Formation of a depot within the plasmalemma seems to require high topical
concentrations of formoterol in the bronchi. This is thought to explain why inhaled
formoterol has a longer duration of action than when given orally, as the inhaled route
achieves higher topical concentration in the periciliary fluid of the bronchi (4).