Structure−Activity Studies of the Melanocortin Peptides:  Discovery of Potent and Selective Affinity Antagonists for the<i>h</i>MC3 and<i>h</i>MC4 Receptors

Grieco, Paolo; Lavecchia, Antonio; Cai, Minying; Trivedi, Dev; Weinberg, David H.; MacNeil, Tanya; Ploeg, Lex H.T. Van der; Hruby, Victor J.

doi:10.1021/jm0202526

Cited by 71 publications

(119 citation statements)

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“…11 Upon substitution of His 6 in SHU9119, a potent hMC3R/hMC4R antagonist (Ac-Nle-c[Asp-His-D-Nal(2′)-Arg-Trp-Lys]-NH 2 ), 12 by conformationally restricted amino acids, selective antagonists for the hMC3R and hMC4R were discovered. 13 In particular, several conformationally constricted amino acids such as Tic, Oic, Aic, etc., were introduced and subsequently provided information about well-defined conformational spaces. 13 Upon substitution of His 6 by Tic a potent hMC3R (IC 50 = 6.7 nM) and hMC4R (IC 50 = 3.7 nM) antagonist was obtained.…”

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confidence: 99%

“…13 In particular, several conformationally constricted amino acids such as Tic, Oic, Aic, etc., were introduced and subsequently provided information about well-defined conformational spaces. 13 Upon substitution of His 6 by Tic a potent hMC3R (IC 50 = 6.7 nM) and hMC4R (IC 50 = 3.7 nM) antagonist was obtained. This work along with that of others 14-16 provided clear evidence of the importance of position 6 for potency and melanocortin receptor selectivity in analogues of α-MSH.…”

mentioning

confidence: 99%

“…The strategy of performing the peptide cyclization prior to removal of the N α -Fmoc protecting group of the Asp residue was chosen to minimize the competing aspartimide formation, as recently suggested by Flora et al, 33 and indeed was found to be superior to the previously reported procedure. 13 The peptides were isolated and purified as described previously 27 in 30-35% overall yield and were >95% pure as determined by analytical RP-HPLC. The structures of the pure peptides were confirmed by high-resolution electrospray ionization (ESI) mass-spectrometry.…”

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confidence: 99%

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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

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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...

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confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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

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“…2) [61]. The biological results of this series of compounds clearly indicate that a conformational restriction with bulky amino acids in position 6 in a cyclic peptide can be used to obtain selective antagonists for the hMC3R and the hMC4R (pA 2 = 9.1-9.8) [61]. (Table 1) [63].…”

Section: Global and Local Conformational Constraints In The Design Ofmentioning

confidence: 83%

“…This structural feature was hypothesized to be very important for receptor-ligand recognition and interaction. Grieco et al had found that replacement of the His 6 residue in SHU9119 template with a variety of conformationally constrained amino acids leads to substantially improved receptor selectivity (Table 1) [61,68]. On the basis of these results, Grieco et al suggested that the improvement in receptor selectivity was due to differences between the hMC3R and hMC4R binding pockets, which are able to accommodate amino acid residues with different conformational profiles.…”

Section: Using Nmr Based Modeling and Computational Methods For Melanmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Ligands Selective for the Melanocortin-3 Receptor

Hruby¹,

Cai²,

Cain³

et al. 2007

curr top med chem

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The processed products of the proopiomelanocortin gene (ACTH, α-MSH, β-MSH, γ-MSH, etc.) interact with five melanocortin receptors, the MC1R, MC2R, MC3R, MC4R, and MC5R to modulate and control many important biological functions crucial for good health both peripherally (as hormones) and centrally (as neurotransmitters). Pivotal biological functions include pigmentation, adrenal function, response to stress, fear/flight, energy homeostasis, feeding behavior, sexual function and motivation, pain, immune response, and many others, and are believed to be involved in many disease states including pigmentary disorders, adrenal disorders, obesity, anorexia, prolonged and neuropathic pain, inflammatory response, etc. The roeianocortin-3 receptor (MC3R) is found primarily in the brain and spinal cord and also in the periphery, and its biological functions are still not well understood. Here we review some of the biological functions attributed to the MC3R, and then examine in more detail efforts to design and synthesize ligands that are potent and selective for the MC3R, which might help resolve the many questions still remaining about its function. Though some progress has been made, there is still much to be done in this critical area.

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Fixierung cyclischer Peptide: Mimetika von Proteinstrukturmotiven

et al. 2014

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Viele Proteine entfalten ihre biologische Aktivität über kleine exponierte Oberflächenregionen aus gefalteten Peptiden mit wohldefinierten dreidimensionalen Strukturen, Epitope genannt. Kurze synthetische Peptidsequenzen, die diesen bioaktiven Proteinoberflächen entsprechen, bilden in Wasser keine thermodynamisch stabilen proteinähnlichen Strukturen. Die Bildung proteinähnlicher biologisch aktiver Konformationen (Stränge, Helices, Kehren) kann jedoch durch Cyclisierung in Verbindung mit anderen molekularen Verstrebungen induziert werden. Letztere helfen bei der Feinabstimmung der dreidimensionalen Struktur. Solche fixierten cyclischen Peptide können ähnliche biologische Aktivitäten und Wirkungen wie das als Vorbild dienende Protein haben, sodass sie als biologische Sonden und Leitstrukturen für Therapeutika, Diagnostika und Impfstoffe dienen können. Dieser Aufsatz beleuchtet Beispiele für cyclische Peptide, die dreidimensionale Strukturen von Strang‐, Kehren‐ oder Helixabschnitten von Peptiden und Proteinen nachahmen und beschreibt einige weitere Elemente, die in cyclisch peptidischen Naturstoffen und synthetischen makrocyclischen Peptidomimetika vorkommen, dort die Peptidstruktur verfeinern und ihr biologische Aktivitäten verleihen.

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Structure−Activity Studies of the Melanocortin Peptides: Discovery of Potent and Selective Affinity Antagonists for thehMC3 andhMC4 Receptors

Cited by 71 publications

References 53 publications

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

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

Design, Synthesis and Biological Evaluation of Ligands Selective for the Melanocortin-3 Receptor

Fixierung cyclischer Peptide: Mimetika von Proteinstrukturmotiven

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