Human melanocortin 4 receptor (hMC4R) mutations with in vitro functional effects are responsible for 0 . 5-2 . 5% of severe obesity. Designing ligands that are able to counteract this in vitro-associated molecular defect is crucial to develop specific anti-obesity drugs in these genetically associated cases. We analyzed the in vitro effect of two novel melanocortin agonists, IRC-022493 and IRC-022511, on typical hMC4R mutations chosen based on the nature of their functional alterations, i.e. intracytoplasmic retention and/or reduced basal activity and/or reduced a-MSH potency. We assessed the in vitro ability of IRC-022493 and IRC-022511 to bind and activate hMC4R mutants. These mutations were found earlier in 11 obese French patients (median age (range) was 17 . 6 years (5 . . 0) and body mass index (BMI)-Z-score 4 . 2 S.D. (1 . 5-5 . 5). The MC4R agonists were responsible for a significant activation of mutated hMC4R depending on the functional characteristics of the mutations. Both agonists were able to activate mutated hMC4R with decreased a-MSH potency, associated with or without decreased basal activity, to the same extent than a-MSH in wild-type MC4R. This result suggests that those mutations would be the best targets for the MC4R agonists among MC4R mutation-bearing obese patients. No specific clinical phenotype was associated with the differential response to pharmacological agonists. We identified two novel melanocortin agonists that were able in vitro to efficiently activate mutated hMC4R with impaired endogenous agonist functional response. These results stimulate interest in the development of these drugs for hMC4R mutations-associated obesity.