RESUMEN
The solution structures and inter-molecular interaction of the cyclic melanocortin antagonists SHU9119, JKC363, HS014, and HS024 with receptor molecules have been determined by NMR spectroscopy and molecular modeling. While SHU9119 is known as a nonselective antagonist, JKC363, HS014, and HS024 are selective for the melanocortin subtype-4 receptor (MC4R) involved in modulation of food intake. Data from NMR and molecular dynamics suggest that the conformation of the Trp9 sidechain in the three MC4R-selective antagonists is quite different from that of SHU9119. This result strongly supports the concept that the spatial orientation of the hydrophobic aromatic residue is more important for determining selectivity than the presence of a basic, "arginine-like" moiety responsible for biological activity. We propose that the conformation of hydrophobic residues of MCR antagonists is critical for receptor-specific selectivity.
Asunto(s)
Hormonas Estimuladoras de los Melanocitos/química , Péptidos Cíclicos/química , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Receptores de Melanocortina/antagonistas & inhibidores , Secuencia de Aminoácidos , Sitios de Unión , Interacciones Farmacológicas , Interacciones Hidrofóbicas e Hidrofílicas , Espectroscopía de Resonancia Magnética , Hormonas Estimuladoras de los Melanocitos/síntesis química , Hormonas Estimuladoras de los Melanocitos/farmacología , Modelos Moleculares , Datos de Secuencia Molecular , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/farmacología , Receptor de Melanocortina Tipo 4/efectos de los fármacos , Receptores de Melanocortina/efectos de los fármacos , Sensibilidad y Especificidad , Soluciones/química , Relación Estructura-Actividad , beta-MSH/síntesis química , beta-MSH/química , beta-MSH/farmacologíaRESUMEN
This review documents my research for the past 45 years in peptide chemistry. Initially, in order to study the structure-activity relationships of active center of alpha- and beta-melanocyte stimulating hormones (H-His-Phe-Arg-Trp-Gly-OH), we employed D-amino acids. That approach yielded first published report in 1965 of antagonists containing D-amino acids. Monkey beta-melanocyte stimulating hormone (beta-MSH), an 18 amino acid peptide stimulated pigment cells. We synthesized beta-MSH and fragments thereof, and studied in detail structure-activity relationships. A major and valuable result revealed that the C-terminal pentadecapeptide of beta-MSH exhibited higher MSH activity than the parent hormone providing a new question; namely, what was the role of the N-terminal tripeptide? In order to identify the novel enzyme, spleen fibrinolytic proteinase (SFP), I developed a specific chromogenic substrate, Suc-Ala-Tyr-Leu-Val-pNA, and a specific inhibitor, Suc-Tyr-D-Leu-D-Val-pNA, once again employing my D-amino acid strategy. SFP was purified by affinity chromatography using Suc-Tyr-D-Leu-D-Val-pNA as the bound ligand. The success of this approach provided me the incentive to develop a variety of potential drugs. Thus, I prepared a specific plasmin inhibitor (YO-2) and a plasma kallikrein inhibitor (PKSI-527). Next, my research developed novel opioid receptor specific opioid agonists and antagonists based on 2',6'-dimethyl-L-tyrosine (Dmt) dimers coupled with unique pyrazinone ring as a spacer. They exhibited potent oral antinociceptive activity acting through the mu-opioid receptor. Potent mu-receptor agonists (H-Dmt-Pro-Phe/Trp- Phe-NH(2)) were transformed into highly selective mu-receptor antagonists (N-allyl-Dmt-Pro-Phe/Trp-Phe-NH(2)), which reversed ethanol-induced increases in GABAergic neurotransmission, suggesting the possibility that they may emerge as candidates for the treatment of ethanol addiction.
Asunto(s)
Aminoácidos , Hormonas Estimuladoras de los Melanocitos , Péptidos/síntesis química , Receptores Opioides mu , Alcoholismo/tratamiento farmacológico , Descubrimiento de Drogas , Humanos , Hormonas Estimuladoras de los Melanocitos/síntesis química , Hormonas Estimuladoras de los Melanocitos/farmacología , Péptidos/química , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inhibidores , Relación Estructura-Actividad , beta-MSH/síntesis química , beta-MSH/farmacologíaRESUMEN
The recent emergence of obesity as a major health threat in the industrialized world has intensified the search for novel and effective pharmacologic treatment. The proopiomelanocortin (POMC)-melanocortin 4 receptor (MC4R) axis has been shown to regulate food intake and energy homeostasis and is considered among the most promising antiobesity targets. Our initial efforts in this area have focused on affinity and selectivity directed optimization of the native beta-MSH(5-22) sequence and resulted in the discovery of a potent MC4R agonist: Ac-Tyr-Arg-[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH(2) (10). Subcutaneous administration of this peptide produced an excellent in vivo efficacy in reducing food intake and increasing fat metabolism. Additionally, suppression of food intake was observed in wild type but not in MC4R deficient mice, suggesting that the effects observed in the wild type mice were mediated through MC4R signaling. Subsequent optimization efforts led to the identification of a novel series of disulfide constrained hexapeptides as exemplified by Ac-[hCys-His-D-Phe-Arg-Trp-Cys]-NH(2) (100). These cyclic hexapeptides showed a further improved potency in binding MC4R and an enhanced selectivity over MC1R. At a dose of 0.07 mg/kg analog 102 reduced food intake by 38% and increased fat utilization by 58% in rats. These cyclic peptides provide novel and enhanced reagents for the elucidation of melanocortin receptors biology and may find applications in the treatment of obesity and related metabolic disorders.