Distinct binding and signaling activity of Acthar Gel compared to other melanocortin receptor agonists

Purpose To compare the binding and agonistic activity of Acthar (R) Gel and synthetic melanocortin receptor (MCR) agonists and examine how the activity of select agonists affects thein vivoproduction of corticosterone. Materials and Methods In vitrobinding was determined using concentration-dependent displacement of the ligand [I-125]Nle(4), D-Phe(7)-alpha-melanocyte-stimulating hormone (alpha-MSH) on cells expressing MC1R, MC3R, MC4R, or MC5R. Functional activity was determined using a time-resolved fluorescence cyclic adenosine monophosphate (cAMP) assay in cells expressing MC1R, MC2R, MC3R, MC4R, or MC5R.In vivocorticosterone analyses were performed by measuring plasma corticosterone levels in Sprague Dawley rats. Results Acthar Gel and synthetic MCR agonists exhibited the highest binding at MC1R, lowest binding at MC5R, and moderate binding at MC3R and MC4R. Acthar Gel stimulated the production of cAMP in all 5 MCR-expressing cell lines, with MC2R displaying the lowest level of full agonist activity, 3-, 6.6-, and 10-fold lower than MC1R, MC3R, and MC4R, respectively. Acthar Gel was a partial agonist at MC5R. The synthetic MCR agonists induced full activity at all 5 MCRs, with the exception of alpha-MSH having no activity at MC2R. Acthar Gel treatment had less of an impact onin vivoproduction of corticosterone compared with synthetic ACTH(1-24)depot. Conclusions Acthar Gel bound to and activated each MCR tested in this study, with partial agonist activity at MC5R and the lowest level of full agonist activity at MC2R, which distinguished it from synthetic MCR agonists. The minimal activity of Acthar Gel at MC2R corresponded to lower endogenous corticosteroid production.

Automated summary

The study compared the binding and agonistic activity of Acthar Gel and synthetic MCR agonists, finding that Acthar Gel exhibited different activity levels in various MCRs. Specifically, it showed the lowest level of full agonist activity at MC2R, which may result in lower corticosteroid production.