Structure–Activity Relationships of Cyclic Lactam Analogues of α-Melanocyte-Stimulating Hormone (α-MSH) Targeting the Human Melanocortin-3 Receptor

A variety of dicarboxylic acid linkers introduced between the α-amino group of Pro<sup>6</sup> and the ϵ-amino group of Lys<sup>10</sup> of the cyclic lactam α-melanocyte-stimulating hormone (α-MSH)-derived Pro<sup>6</sup>-d-Phe<sup>7</sup>/d-Nal(2′)<sup>7</sup>-Arg<sup>8</sup>-Trp<sup>9</sup>-Lys<sup>10</sup>-NH<sub>2</sub> pentapeptide template lead to nanomolar range and selective hMC3R agonists and antagonists. Replacement of the Pro<sup>6</sup> residue and the dicarboxylic acid linker with 2,3-pyrazine-dicarboxylic acid furnished a highly selective nanomolar range hMC3R partial agonist (analogue <b>12</b>, c[CO-2,3-pyrazine-CO-d-Phe-Arg-Trp-Lys]-NH<sub>2</sub>, EC<sub>50</sub> = 27 nM, 70% max cAMP) and an hMC3R antagonist (analogue <b>13</b>, c[CO-2,3-pyrazine-CO-d-Nal(2′)-Arg-Trp-Lys]-NH<sub>2</sub>, IC<sub>50</sub> = 23 nM). Modeling experiments suggest that 2,3-pyrazinedicarboxylic acid stabilizes a β-turn-like structure with the d-Phe/d-Nal(2′) residues, which explains the high potency of the corresponding peptides. Placement of a Nle residue in position 6 produced a hMC3R/hMC5R antagonist (analogue <b>15</b>, c[CO-(CH<sub>2</sub>)<sub>2</sub>-CO-Nle-d-Nal(2′)-Arg-Trp-Lys]-NH<sub>2</sub>, IC<sub>50</sub> = 12 and 17 nM, respectively), similarly to the previously described cyclic γ-melanocyte-stimulating hormone (γ-MSH)-derived hMC3R/hMC5R antagonists. These newly developed melanotropins will serve as critical biochemical tools for elucidating the full spectrum of functions performed by the physiologically important melanocortin-3 receptor.