It's never easy finding clinically relevant ligands for receptors. Although you might have identified an appropriate receptor to target, you soon find out from preclinical models that as well as being involved in the pathway of interest, it is involved in other pathways that will produce unwanted side effects. But, according to a study by Limbird and colleagues in Proceedings of the National Academy of Sciences, the key to sorting out the physiological wheat from the chaff might be to characterize the physiological and behavioural responses in mouse models that are heterozygous for the receptor of interest.

The authors looked at the α2A-adrenoceptor (α2A-AR), as genetic manipulation of this receptor in mice had shown that it was involved in several responses — both clinically desired (for example, hypotension) and unwanted (for example, sedation). So, they were surprised to find that in heterozygous models (α2A-AR+/− mice) supramaximal doses of α2A-agonists lowered blood pressure without affecting sedation, implying that more than 50% of α2A-AR must be activated to cause sedation.

Limbird and colleagues hypothesized that differing fractional activation of receptors by using partial agonists (or alternatively by administering incremental doses of a full agonist) could produce these selective responses. This idea was supported by the fact that moxonidine (which the authors showed to be a partial agonist in in vitro studies) has no hypotensive effects in α2A-AR-null mice but lowers blood pressure without sedation in wild-type mice.

So, the authors say that weak partial agonists could be used to achieve α2A-AR pharmacotherapy when the sedation effects are not wanted; for example, in the treatment of depression or attention-deficit hyperactivity disorder. And given that members of several receptor families — including G-protein-coupled receptors and nuclear hormone receptors — also show fractional activation properties, this method could also be used in mouse models that are heterozygous for other receptors to identify response-specific agents for various disease states.