Ligand

The word is deliberately neutral. Agonists, partial agonists, antagonists, inverse agonists, allosteric modulators and inert radiolabelled tracers are all ligands, and the category is defined only by specific, saturable binding to a defined site. Ligands are split into endogenous ones the organism makes, such as hormones and neurotransmitters, and exogenous ones introduced from outside, including every drug. The receptor's endogenous ligand is the reference against which analogues are described as more or less potent, more or less selective, and longer or shorter acting.

A receptor with no known endogenous ligand is called an orphan, and the process of finding one is called deorphanisation. The growth hormone secretagogue field ran this sequence in an unusual order. Synthetic peptides such as GHRP-6 were shown to release growth hormone before anyone knew what they bound; the receptor they acted on was cloned in 1996; and only in 1999 was the natural ligand, ghrelin, isolated from stomach tissue by working backwards from the receptor. The peptide drug preceded both its receptor and its hormone by two decades.

Identifying the endogenous ligand is what converts a screening hit into physiology, because it tells you what system the compound is borrowing and therefore what regulation, feedback and counter-regulation it will run into. Without it, a compound has an activity but no context.

Where the term misleads is in promotion. Describing a peptide as a ligand for a named receptor sounds like a mechanism but asserts only that it sticks, and some of these claims trace back no further than a computational docking image rather than a binding experiment. The word also has an unrelated meaning in coordination chemistry, where it denotes a group bound to a metal centre, which is occasionally exploited to make a chelator sound like a receptor drug.