Structure and activity of conopressins: insights into in silico oxytocin/V2 receptor interactions, anti-inflammatory potential, and behavioural studies†

Conopressins are single disulfide conopeptides with a close sequence similarity to vasopressin and oxytocin, exhibiting grooming and scratching effects in rodents. Here, we have investigated the impact of stereochemistry on the conserved arginine residue at position 4 and the truncation (Tr-Mo976 and Tr-Mo977) on the structure and activity of conopressins. 3D structures determined by solution NMR revealed distinct structural features for Mo1033 and ^DR4-Mo1033. Molecular dynamics studies of the conopressins with oxytocin and V2 receptor complexes revealed that both Tr-Mo976 and Tr-Mo977 showed robust interactions with the OT receptor and reduced interactions with the V2 receptor. In addition, conopressins exhibited anti-inflammatory and antioxidant potential in LPS-stimulated macrophages. Behavioural studies in mice demonstrated high grooming and scratching behaviour for Tr-Mo976 and reduced locomotory activity with Tr-Mo977. To this end, results suggest that both the truncation of the tail region and the nature of residue 8 play an essential role in altering the activity of conopressins.