Receptor Selectivity
Receptor selectivity is the degree to which a ligand acts on its intended receptor rather than related ones, expressed as the ratio between its potency at the target and at each off-target.
Selectivity is a ratio, not a property a molecule has or lacks. It is stated as the fold difference between the concentration needed at the intended receptor and at a comparator — a hundred-fold selective ligand reaches its target at concentrations a hundred times below those engaging the other. Because receptor families share ancestry and pocket architecture, selectivity is hardest exactly where it matters most: among subtypes differing by a handful of residues.
The melanocortin family shows the cost of imperfect selectivity. MC1R through MC5R respond to overlapping ligands, so agonists developed for MC4R-mediated effects also engage MC1R on melanocytes, and the resulting pigmentation is a predictable pharmacological consequence. Somatostatin analogues make the point in reverse: octreotide is weighted toward SSTR2 with some SSTR5 activity, while pasireotide binds a broader set of subtypes, and the coverage difference shows up in their glycaemic profiles.
Selectivity means something only relative to concentrations actually achieved. A hundred-fold selective compound is effectively selective at a dose reaching the target's EC50 and effectively non-selective at ten times that dose, so the useful question is how much of the ratio the dosing range consumes.
The claim to distrust is highly selective offered without a ratio, a counter-target panel or the concentrations tested. Selectivity against three related receptors says nothing about the several hundred not screened, and binding selectivity is not functional selectivity — a ligand can bind two receptors equally and activate only one. Functional selectivity in the literature usually means biased agonism at a single receptor, a distinct idea routinely conflated with subtype selectivity.