Melanocortin 1 Receptor Agonists Based on a Bivalent, Bicyclic Peptide Framework.

Journal of medicinal chemistry 2021 Jul 22

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We have designed a new class of highly potent bivalent melanocortin receptor ligands based on the nature-derived bicyclic peptide sunflower trypsin inhibitor 1 (SFTI-1). Incorporation of melanotropin pharmacophores in each of the two turn regions of SFTI-1 resulted in substantial gains in agonist activity particularly at human melanocortin receptors 1 and 3 (hMC1R/hMC3R) compared to monovalent analogues. In in vitro binding and functional assays, the most potent molecule, compound 6, displayed low picomolar agonist activity at hMC1R (pEC50 > 10.3; EC50 < 50 pM; pKi: 10.16 ± 0.04; Ki: 69 ± 5 pM) and is at least 30-fold more selective for this receptor than for hMC3R, hMC4R, or hMC5R. The results are discussed in the context of structural homology models of hMCRs in complex with the developed bivalent ligands.

Citation

Thomas Durek, Quentin Kaas, Andrew M White, Joachim Weidmann, Abdullah Ahmad Fuaad, Olivier Cheneval, Christina I Schroeder, Simon J de Veer, Anita Dellsén, Torben Österlund, Niklas Larsson, Laurent Knerr, Udo Bauer, Alleyn T Plowright, David J Craik. Melanocortin 1 Receptor Agonists Based on a Bivalent, Bicyclic Peptide Framework. Journal of medicinal chemistry. 2021 Jul 22;64(14):9906-9915