Development of Cyclic γ-MSH Analogues with Selective hMC3R Agonist and hMC3R/hMC5R Antagonist Activities

Mayorov, Alexander V.; Cai, Minying; Chandler, Kevin Brown; Petrov, Ravil R.; Scoy, April R. Van; Yu, Zerui; Tanaka, Dustin K.; Trivedi, Dev; Hruby, Victor J.

doi:10.1021/jm0510326

Cited by 34 publications

(63 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings suggest an essential role for His 6 for potent full agonist activity of the peptides derived from this template, which sets it apart from other previously reported cyclic α-and γ-MSH templates that have been demonstrated to have no such structural requirement for His 6 . 37 The β-turn position shift observed in our molecular modeling experiments may prove to be highly beneficial as another approach for development of highly selective melanocortin receptor agonists and antagonists. Subsequently, we synthesized a series of compounds (2−19, Table 1) where we performed modifications at positions 6−9 by replacing with several different amino acids to obtain a rational SAR study.…”

Section: Resultsmentioning

confidence: 86%

“…37 Peptide structures were built into extended structures with standard bond lengths and angles, and they were minimized using the OPLS 2005 force field 41 and the Polak-Ribier conjugate gradient (PRCG). Optimizations were converged to a gradient rmsd less that 0.05 kJ/Å mol or continued until a limit of 50000 iterations was reached.…”

Section: Computational Proceduresmentioning

confidence: 99%

See 1 more Smart Citation

Design and Microwave-Assisted Synthesis of Novel Macrocyclic Peptides Active at Melanocortin Receptors: Discovery of Potent and Selective hMC5R Receptor Antagonists

Grieco

Cai

et al. 2008

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

Differentiation of the physiological role of the melanocortin receptor 5 MC5R from that of other melanocortin receptors will require development of high affinity and selective antagonists. To date, a few synthetic antagonist ligands active at hMC5 receptor are available, but most do not have appreciable selectivity. With the aim to gain more potent and selective antagonists for the MC5R ligands, we have designed, synthesized, and pharmacologically characterized a series of alkylthioaryl-bridged macrocyclic peptide analogues derived from MT-II and SHU9119. These 20-membered macrocycles were synthesized by a tandem combination using solid phase peptide synthesis and microwave-assisted reactions. Biological assays for binding affinities and adenylate cyclase activities for the hMC1R, hMC3R, hMC4R, and hMC5R showed that three analogues, compounds, 9, 4, and 7, are selective antagonists at the hMC5 receptor. In particular, compound 9 (PG-20N) is a selective and competitive hMC5R antagonist, with IC 50 of 130 ± 11 nM, and a pA 2 value of 8.3, and represents an important tool for further biological investigations of the hMC5R. Compounds 4 and 7 (PG14N, PG17N) show potent and selective allosteric inhibition at hMC5R with IC 50 values of 38 ± 3 nM and 58 ± 6 nM, respectively. Compound 9 will be used to further investigate and more clearly understand the physiological roles played by the MC5 receptor in humans and other animals.

show abstract

Section: Resultsmentioning

confidence: 86%

Section: Computational Proceduresmentioning

confidence: 99%

Design and Microwave-Assisted Synthesis of Novel Macrocyclic Peptides Active at Melanocortin Receptors: Discovery of Potent and Selective hMC5R Receptor Antagonists

Grieco

Cai

et al. 2008

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…This study employed Macromodel 9.1, with the OPLS 2005 force field and a MCMM/LMCS (Monte Carlo Multiple Minima/Low Frequency Mode) conformational search method. 27 We overlapped the NMR structure of the cyclic lactam α-MSH analogue MT-…”

mentioning

confidence: 99%

Novel selective human melanocortin-3 receptor ligands: Use of the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffold

Ballet

Mayorov

Cai

et al. 2007

Bioorganic & Medicinal Chemistry Letters

Self Cite

View full text Add to dashboard Cite

In search of new selective antagonists and/or agonists for the human melanocortin receptor subtypes hMC1R to hMC5R to elucidate the specific biological roles of each GPCR, we modified the structures of the superagonist MT-II (Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-NH 2 ) and the hMC3R/hMC4R antagonist SHU9119 (Ac-Nle-c[Asp-His-D-Nal(2′)-Arg-Trp-Lys]-NH 2 ) by replacing the His-D-Phe and His-D-Nal(2′) fragments in MT-II and SHU9119, respectively, with Aba-Xxx (4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one-Xxx) dipeptidomimetics (Xxx = D-Phe/pCl-D-Phe/D-Nal(2′)). Employment of the Aba mimetic yielded novel selective high affinity hMC3R and hMC3R/hMC5R antagonists. KeywordsHuman melanocortin receptors; 4-Amino-1,2,4,5-tetrahydro-2-benzazepin-3-ones; Cyclic lactam analogues; Conformational restrictions; hMC3R/hMC5R antagonists The α-melanocyte stimulating hormone (α-MSH, Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-TrpGly-Lys-Pro-Val-NH 2 ) plays a role in a wide range of biological responses like feeding behavior, pain modulation, learning behavior, pigmentation, sexual function, energy homeostasis, and thermoregulation. 1 In particular, the human melanocortin 4 subtype receptor is an attractive drug target because of its role in regulation of feeding behavior. 2,3 Design of selective hMC4R antagonists is considered to have great potential for the treatment of anorexia. 4,5 The hMC3R on the other hand has been shown to play a role in the physiological process of energy partitioning and body weight. 6 Controlled modulation of these receptors could lead to promising results in the field of feeding disorders.The principal pharmacophore groups of α-MSH were found to be the side chains of the central tetrapeptide His 6 -Phe 7 -Arg 8 -Trp 9 . 7,8 Molecular modeling as well as conformational analysis of a variety of cyclic analogues led to the discovery of a superpotent lactam analogue MT-II (Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-NH 2 ). 9 This cyclic peptide analogue, first introduced by Al-Obeidi et al. 9 was a very potent, but non-selective, agonist for the human melanocortin receptor subtypes MC1R, MC3R, MC4R, and MC5R. It also showed a very high stability against all proteolytic enzymes and tissue homogenates. 9 Because of the lack in selectivity, finding selective ligands for each of the four human melanocortin receptors * Corresponding author. Tel.: +32 26293298; fax: +32 26293 304; e-mail: sballet@vub.ac.be. The 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold (Fig. 1) has proven to be an excellent tool for the design of novel peptide mimetics. 17-22 Its qualities can be described as two folded: (1) the scaffold can be considered as a conformationally restricted Phe analogue where the aromatic side chain is anchored to the α-amine of the next residue by means of a methylene bridge (dotted line); 17 (2) on the other hand, one can see the Aba template as a 'privileged template'. 23 NIH Public AccessIn scaffold 1 only the g(+) (χ 1 = +60°) and trans (χ 1 = 180°) staggered conformations are allowed for the C α -C β bon...

show abstract

“…Competition binding assays and second message cAMP assays for the MC-1, -3, -4, and MC-5 receptors were carried out using HEK-293 cells as previously described. 18,19 First, the Tic residue was truncated to examine its role in binding at both the opioid and MC receptors. Ligand 3 lacking the Tic residue lost its binding affinities for the d opioid and all the MC receptors, while it retained weak binding affinity (6700 nM) at the l opioid receptor (Table II).…”

Section: Resultsmentioning

confidence: 99%

Opioid and melanocortin receptors: Do they have overlapping pharmacophores?

et al. 2008

Self Cite

View full text Add to dashboard Cite

We have identified compound 1 as a novel ligand for opioid and melanocortin (MC) receptors, which is derived from the overlapping of a well known structure for the δ opioid receptor, 2,6‐dimethyltyrosine (Dmt)‐1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid (Tic), and a small molecule for the MC receptor, Tic‐DPhe(p‐Cl)‐piperidin‐4‐yl‐N‐phenyl‐propionamide. Ligand 1 showed that there is an overlapping pharmacophore between opioid and MC receptors through the Tic residue. The ligand displayed high biological activities at the δ opioid receptor (Ki = 0.38 nM in binding assay, EC50 = 0.48 nM in GTP‐γ‐S binding assay, IC50 = 74 nM in MVD) as an agonist instead of an antagonist and showed selective binding affinity (IC50 = 2.3 μM) at the MC‐3 receptor rather than at the MC‐5 receptor. A study of the structure‐activity relationships demonstrated that the residues in positions 2, 3, and the C‐terminus act as a pharmacophore for the MC receptors, and the residues in positions 1 and 2 act as a pharmacophore for the opioid receptors. Thus, this structural construct can be used to prepare chimeric structures with adjacent or overlapping pharmacophores for opioid and MC receptors. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 433–438, 2008.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

show abstract

Development of Cyclic γ-MSH Analogues with Selective hMC3R Agonist and hMC3R/hMC5R Antagonist Activities

Cited by 34 publications

References 54 publications

Design and Microwave-Assisted Synthesis of Novel Macrocyclic Peptides Active at Melanocortin Receptors: Discovery of Potent and Selective hMC5R Receptor Antagonists

Design and Microwave-Assisted Synthesis of Novel Macrocyclic Peptides Active at Melanocortin Receptors: Discovery of Potent and Selective hMC5R Receptor Antagonists

Novel selective human melanocortin-3 receptor ligands: Use of the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffold

Opioid and melanocortin receptors: Do they have overlapping pharmacophores?

Contact Info

Product

Resources

About