By a combination of molecular modelling and site-directed mutagenesis studies, we have recently identified a key residue in the first extracellular loop which determines agonist selectivity and high-affinity binding in the V1a vasopressin receptor. Based on primary sequence analysis and structure-activity relationship studies of other neuropeptides and their receptors, the corresponding amino acid in the first extracellular loop is proposed to play a homologous role in conferring affinity and selectivity. This would seem to be the case notably for angiotensin, cholecystokinin, neuropeptide Y and neurokinin receptors.