Analogs of sub-nanomolar hMC1R agonist LK-184 [Ph(CH2)3CO-His-D-Phe-Arg-Trp-NH2]. An additional binding site within the human melanocortin receptor 1?

Bioorganic & Medicinal Chemistry Letters
L N KoikovJ J Knittel

Abstract

Twenty nine analogs of a superpotent MC1R agonist LK-184 (1) were tested at human melanocortin receptors (hMC1, hMC3, and hMC4Rs). All derivatives with the spacer between the N-terminus and the aromatic ring longer or shorter than C(3) were much less potent at hMC1R than 1. Only LK-312 PhCO(CH(2))(3)CO-His-d-Phe-Arg-Trp-NH(2) (3), partially mimicking the pi-system of 1, had an EC(50) of 0.05 nM at hMC1R, which confirms the localization of the pi-binding zone of the receptor. Truncation of 1 to Ph(CH(2))(3)CO-His-d-Phe-Arg-NH(2) gave a full MC1 agonist, LK-394 (30), with an EC(50) of 5 nM and a weak partial agonism at MC3/4Rs. This suggests the existence of an additional binding site within hMC1R next to that for the core sequence His-d-Phe-Arg-Trp-NH(2).

References

Nov 1, 1987·Journal of Medicinal Chemistry·V J HrubyM F Hintz
May 5, 1995·Biochemical and Biophysical Research Communications·P PrusisJ E Wikberg
Aug 15, 1998·Molecular and Cellular Endocrinology·H B SchiöthJ E Wikberg
Aug 12, 1999·European Journal of Pharmacology·J E Wikberg
Jul 23, 2003·Bioorganic & Medicinal Chemistry Letters·L N KoikovJ J Knittel

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Citations

Jul 23, 2003·Bioorganic & Medicinal Chemistry Letters·L N KoikovJ J Knittel
Jun 30, 2009·Pigment Cell & Melanoma Research·Zalfa A Abdel-MalekJames J Knittel
Dec 27, 2005·Bioorganic & Medicinal Chemistry Letters·Xinrong TianRussell J Sheldon
Jun 2, 2007·Chemical Biology & Drug Design·Aleksandar TodorovicCarrie Haskell-Luevano

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