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The constrained conformation additionally positions the pharmacophore residues (His, D-Phe, Arg, Trp) in an optimal spatial arrangement for simultaneous contact with the MC receptor binding pocket, which is why cyclic melanocortin analogs consistently demonstrate 10-100 fold greater potency than their linear counterparts in cAMP accumulation assays

Low folate and Vitamin C levels may also contribute

ACS Applied Materials and Interfaces

In OCT1, the equivalent interaction is a salt bridge between R486 OCT1 and D149 OCT1, which similarly stabilises the inward-facing conformation

Xue M, Chen X, Guo Z, Liu X, Bi Y, Yin J, et al

However, based on physician assessment using 2-dimensional patient photographs, 11 of 14 patients demonstrated improvement