What Are the Functional Groups in Salbutamol?

Salbutamol is widely used in inhalers for asthma treatment.

Salbutamol is a widely used asthma medication sold under numerous trade names, including Ventolin and Proventil. It is a bronchodilator, meaning that it acts on specific cells in the airway to widen the air passages. Its mechanism of action, which is through interaction with a specific cellular receptor, the beta-2-adrenergic receptor (b-2AR), has been intensely studied. The binding of salbutamol to b-2AR "activates" the receptor, stimulating it to produce chemicals that eventually lead to relaxation of the airway muscles.

How It Works

Salbutamol binds to b-2AR specifically, like a key that fits a specific lock.

Salbutamol is only one of many molecules that binds to and activates b-2AR. Epinephrine (adrenaline) is the natural binding partners for the receptor, and the neurotransmitter dopamine binds to it as well. Several other asthma medications are also b-2AR activators; the drugs known as beta-blockers, including propranolol, bind to b-2AR but do not activate it. The varied effects of these molecules is due to differences in their functional groups and how they bind. B-2AR is a membrane protein that weaves its way from the internal to the external surface of the cell membrane seven times, forming seven very close "stitches" that form a ring. Salbutamol interacts with three of b-2AR's seven transmembrane domains (TMDs).

Overall Structure

The chemical structure of adrenaline is similar to that of salbutamol except it lacks the "t-butyl" group.

Salbutamol's molecular structure is similar to that of epinephrine (adrenaline), which was once also used as an asthma drug. Since adrenaline's structure binds with other receptors throughout the body, however, it caused unpleasant side effects.

Like adrenaline, the salbutamol structure is anchored at one end by a carbon ring with two pendant hydroxyl (OH) groups (called a catechol ring). Opposite of one hydroxyl group is a carbon chain with several more functional groups attached to it: another hydroxyl, an amine (NH), and a bulky hydrocarbon group called a "t-butyl" group. The t-butyl differentiates salbutamol from adrenaline and improves its specificity.

Aromatic Ring

The characteristic scent of hyacinth comes from an aromatic compound called hyacinthin.

The carbon ring of salbutamol has alternating single and double bonds that give it a special electronic property known as "aromaticity." (Many, but not all, aromatic rings actually have characteristic odors, which is the origin of the name.) Aromatic rings are attracted to each other, and the ring of salbutamol is believed to fit into b-2AR near three other aromatic rings in TMD 5 and the extracelllular region of the protein. This is a subtle difference from adrenaline, which binds to a phenylalanine amino acid in TMD 6.

Hydroxyls

Hydroxyl groups are also found in alcohols like ethanol.

The two hydroxyls directly connected with the aromatic ring fit into the b-2AR structure in TMD 5, attracted by three serine amino acids. Hydroxyls are not typically attracted by serines, which also contain hydroxyl groups, but are in this case due to the aromatic ring's special electronic properties. The hydroxyl on the tail nestles into TMD 6, attracted to a slightly positive charge on an asparagine amino acid located there.

Amine and t-Butyl Group

The t-butyl group adds bulk to salbutamol's tail, reducing its ability to bind other receptors.

The amine group has a slight positive charge and is attracted to a negatively-charged aspartic acid amino acid in TMD 3. The bulky t-butyl group attached to the amine fits into the roomy pocket of this TMD and interacts with other non-polar amino acids inside. The b-2AR receptor can receive this extra bulk, whereas other receptors that adrenaline activates cannot. This is key to salbutamol's specificity and reduced side effects relative to adrenaline for asthma treatment.

References

• "Molecular Pharmacology"; 'Induced-Fit' Mechanism for Catecholamine Binding to the β2-Adrenergic Receptor; Renata Del Carmine, Paola Molinari, Maria Sbraccia, Caterina Ambrosio, Tommaso Costa; Aug. 2004
• "Journal of Biological Chemistry"; Probing the β2 Adrenoceptor Binding Site with Catechol Reveals Differences in Binding and Activation by Agonists and Partial Agonists; Gayathri Swaminath, Xavier Deupi, Tae Weon Lee, Wen Zhu, Foon Sun Thian, Tong Sun Kobilka, Brian Kobilka; Apr. 2005
• "The Adrenergic Receptors: In the 21st Century"; Dianne M. Perez; 2005

Resources

• "Chemical and Engineering News"; Salbutamol; Corrine Marasco; 2005
• "Receptor-based drug design"; Paul Leff; 1998
• NIH.gov: "Salbutamol - Substance Summary"