Modified melanocortin tetrapeptide Ac‐His‐dPhe‐Arg‐Trp‐NH₂ at the arginine side chain with ureas and thioureas

Abstract

The Ac-His-dPhe-Arg-Trp-NH2 tetrapeptide is a nonselective melanocortin agonist and replacement of Arg in the tetrapeptide with acidic, basic or neutral amino acids results in reduced potency at the melanocortin receptor (MCR) isoforms (MC1R and MC3-5R). To determine the importance of the positive charge and the guanidine moiety for melanocortin activity, a series of urea- and thiourea-substituted tetrapeptides were designed. Replacement of Arg with Lys or ornithine reduced agonist activity at the mouse mMC1 and mMC3-5 receptors, thus supporting the hypothesis that the guanidine moiety is important for receptor potency, particularly at the MC3-5 receptors. The Arg side chain-modified tetrapeptides examined in this study include substituted phenyl, naphthyl, and aliphatic urea and thiourea residues using a Lys side-chain template. These ligands elicit full-agonist pharmacology at the mouse MCRs examined in this study.

Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa1-Arg-(pI)DPhe-Xaa4-NH2

“…This is in contrast to previous reports on melanocortin tetrapeptides in which the SAR tends to favor MC4R potency over the MC3R. 60-61, 72-73, 76, 81-87 …”

“…A total of nine compounds produced moderate to potent agonist activity (EC 50 < 1000 nM) at the mMC3R, in addition to producing antagonist activity at the mMC4R (7.8 > pA 2 > 5.7). This is in contrast to previous reports on melanocortin tetrapeptides in which the SAR tends to favor MC4R potency over the MC3R. ,,,,,− …”

“…The first and fourth positions were selected for further investigations as part of a double-substitution set of analogues and to perform an SAR campaign. It was hypothesized that the second and third positions should be held constant [(Ac-Xaa 1 -Arg-(pI)­DPhe-Xaa 4 -NH 2 ] because previous studies on the linear truncated tetra- and pentapeptide analogues of α-MSH, Ac-His-DPhe-Arg-Trp-NH 2 , and Bu-His-DPhe-Arg-Trp-Gly-NH 2 , indicated alterations at these positions (corresponding to the DPhe and Arg positions in each of the peptides) within the His-Phe-Arg-Trp signaling motif were generally detrimental to the activity at all of the receptors. − The substitutions selected for the analogues herein contain both natural and unnatural amino acids which have been previously reported to alter either the selectivity and/or the potency at the selected melanocortin receptor subtypes in the linear Ac-His-DPhe-Arg-Trp-NH 2 peptide (Figure ). ,, For the first position of the tetrapeptide, arginine (Arg), histidine (His), biphenylalanine (Bip), β-(3-benzothienyl)-alanine (3Bal), 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), phenylalanine (Phe), and d / l -2-naphthylalanine [DNal(2′) and LNal(2′)] were selected (Figure ).…”

Identification of Tetrapeptides from a Mixture Based Positional Scanning Library That Can Restore nM Full Agonist Function of the L106P, I69T, I102S, A219V, C271Y, and C271R Human Melanocortin-4 Polymorphic Receptors (hMC4Rs)

“… 42 − 56 However, it was noted in a few reports that the Arg residue could be replaced by Ala or other residue/side chain modifications and still retain agonist functionality at the melanocortin receptors. 25 , 55 , 57 Herein, the 4 and 8 are further unanticipated examples of melanocortin ligands; specifically, they are tetrapeptides that do not contain the Arg side chain moiety and are still full agonists at the melanocortin receptors. Surprisingly, these two tetrapeptides are not only sub-nM to nM full agonists at the mMC1, mMC3–5Rs (Table 6 ), but they also possess nM full agonist potency at all the six the polymorphic hMC4Rs examined in this study (Tables 4 and 5 ).…”

Structure-Activity Relationships (SAR) of Melanocortin and Agouti-Related (AGRP) Peptides

“…Positional scanning of the Arg position has shown that the guanidine side chain of Arg is important for ligand receptor interactions in peptide ligands (peptides 7 and 8, Table 5). 33 In a similar study, a series of pentapeptides, based on the hMC4R agonist (Ac-His 6 -dPhe 7 -Arg 8 -Trp 9 -Gly 10 -NH 2 ), were synthesized in which either dPhe 7 or Trp 9 residue systematically substituted. 34 A number of interesting dPhe surrogates [dThi, (3-CF 3 ) dPhe, 2-dNal and (3, dPhe)] as well as Trp surrogates (2-Nal and Bta) were identified in this study.…”