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

Abstract

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...

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

“…Reports on MC3R selective compounds have been primarily limited to analogs of α-MSH and γ-MSH. 41-46 The identification of selective MC3R compounds with more drug-like properties, may result in the development of a valuable therapeutic strategy for the current obesity epidemic, as compared to a therapeutic targeting of the activation of the MC4R which has several undesirable side effects.…”

Approaches to the rational design of selective melanocortin receptor antagonists

“…A further improvement for the MC3R in addition to the cis olefin bridged compound 7 [43] was the bridged heterocyclic 2,3-pyrazine-containing compound (data not shown [43]). The cyclic lactam analog containing the special Aba residue (compound 8 , Table 3) had > 200-fold selectivity against the MC1R and the MC4R, and to a lesser extent the MC5R, and was a potent antagonist at the MC3R [44]. Interestingly, the Aba-D-Nal(2′) analog (data not shown, [44]) displayed high affinity hMC3R and hMC5R antagonist properties (IC 50 = 43 and 87 nM, respectively), but weak binding affinity for the hMC4R (IC 50 = 1.7 μM).…”

“…The cyclic lactam analog containing the special Aba residue (compound 8 , Table 3) had > 200-fold selectivity against the MC1R and the MC4R, and to a lesser extent the MC5R, and was a potent antagonist at the MC3R [44]. Interestingly, the Aba-D-Nal(2′) analog (data not shown, [44]) displayed high affinity hMC3R and hMC5R antagonist properties (IC 50 = 43 and 87 nM, respectively), but weak binding affinity for the hMC4R (IC 50 = 1.7 μM). The observed lack of agonist activity at the hMC3R points to possible steric interference from Aba.…”

Melanotropins as Drugs for the Treatment of Obesity and Other Feeding Disorders: Potential and Problems

“…1) is substituted for His in the MT-II scaffold [75]. The analogue of MT-II ( 9 , Table 2), Ac-Nle-c[Asp-Aba-D-Phe-Arg-Trp-Lys]-NH 2 was found to be a potent hMC3R antagonist with greater than 200-fold selectivity vs the hMC4R and hMC1R and about 60-fold selectivity vs the hMC3R.…”