Researchers working in Australia have uncovered why highly similar drugs sometimes produce very different responses. Understanding these variations is key to developing drugs with a strong therapeutic effect and minimal side effects.
Generally, drugs work by interacting with specific proteins - known as receptors – on the surfaces of cells. These interactions cause changes in cell signaling that allow the body to respond to medicine. The overall goal of drug design is to create molecules that bind to specific receptors to cause distinct changes in cells. But molecules designed to bind to the same receptor can affect cells in unexpected ways.
These unintended effects can result from biased agonism. This occurs when drugs designed to target the same receptor end up binding to the receptor at slightly different positions, causing activation of unique signaling pathways. This bias offers a potential therapeutic advantage by allowing preferential activation of beneficial versus harmful cellular responses.
The team uncovered a form of biased agonism when comparing five drugs designed to activate alpha 1A-adrenergic receptors. Alpha 1A-receptors are found throughout the body and primarily control smooth muscle contraction. Drugs targeting these receptors are used to do everything from increasing blood pressure to relieving sinus congestion.
Four of the drugs produced similar effects on a common cell line expressing alpha 1-A receptors: they increased levels of calcium and cAMP - two important signaling molecules - and moderately activated the proteins ERK 1 and ERK 2, which regulate many cellular processes. But the drug oxymetazoline produced a different effect. It did not increase levels of Ca2+ or cAMP yet strongly activated ERK1 and 2.
Interestingly, oxymetazoline targeted an entirely different receptor in addition to alpha 1A-receptors: the 5-HT1B receptor, which was responsible for the distinct profile. In another cell line lacking 5-HT1B receptors, oxymetazoline no longer strongly activated ERK1 and 2.
These findings show how important it is to know what receptors are actually targeted by drugs. Although a drug may be designed for a single purpose, unintended behavior may result at the cellular level. Understanding this behavior is key to designing drugs that work as intended while minimizing side effects.