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Liang Zeng Yan,
Kirk W Johnson,
Emily Rothstein, David Flora,
Patrick Edwards,
Baolin Li,
Junqing Li,
Renee Lynch,
Renee Vaughn,
Amy Clemens-Smith,
Deborah McCarty,
Charles Chow,
Kevin L McKnight,
Jirong Lu,
Eric S Nisenbaum,
John P Mayer
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ABSTRACT: Calcitonin gene-related peptide (CGRP), a potent dilator of cerebral and dural vasculature, is known to be elevated in plasma and cerebral spinal fluid during migraine attacks. Selective blockade of the CGRP receptor offers the promise of controlling migraine headache more effectively and without the side-effects associated with the use of triptans. Our efforts to develop a novel, peptide-based CGRP antagonist focused on the C-terminal portion of the peptide which is known to bind the receptor but lack agonist properties. Extensive SAR studies of the C-terminal CGRP (27-37) region identified a novel cyclic structure: Bz-Val-Tyr-cyclo[Cys-Thr-Asp-Val-Gly-Pro-Phe-Cys]-Phe-NH(2) (23) with a kb value of 0.126 nM against the cloned human CGRP receptor. Additional SAR studies directed at enhancement of potency and improvement of physicochemical properties yielded a series of analogs with kb values in the 0.05-0.10 nM range.
Journal of Peptide Science 03/2011; 17(5):383-6. · 1.80 Impact Factor
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Liang Zeng Yan,
Hansen M Hsiung,
Mark L Heiman,
Robert A Gadski,
Paul J Emmerson,
JeAnne Hertel, David Flora,
Patrick Edwards,
Dave Smiley,
Lianshan Zhang,
Saba Husain,
Steven D Kahl,
Richard D DiMarchi,
John P Mayer
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ABSTRACT: 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.
Current topics in medicinal chemistry 02/2007; 7(11):1052-67. · 4.47 Impact Factor
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Liang Z Yan, David Flora,
Patrick Edwards,
David L Smiley,
Paul J Emmerson,
Hansen M Hsiung,
Robert Gadski,
JeAnne Hertel,
Mark L Heiman,
Saba Husain,
Thomas P O'Brien,
Steven D Kahl,
Lianshan Zhang,
Richard D Dimarchi,
John P Mayer
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ABSTRACT: Extensive structure-activity relationship studies utilizing a beta-MSH-derived cyclic nonapeptide, Ac-Tyr-Arg-[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH(2) (3), led to identification of a series of novel MC-4R selective disulfide-constrained hexapeptide analogs including Ac-[hCys-His-D-Phe-Arg-Trp-Cys]-NH(2) (12). The structural modifications associated with profound influence on MC-4R potency and selectivity were ring size, ring conformation, and the aromatic substitution of the D-Phe7. These cyclic peptide analogs provide novel and enhanced reagents for use in the elucidation of melanocortin-4 receptor-related physiology, and may additionally find application in the treatment of obesity and related metabolic disorders.
Bioorganic & Medicinal Chemistry Letters 11/2005; 15(20):4611-4. · 2.55 Impact Factor
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ABSTRACT: Extensive two-dimensional NMR analysis was employed to characterize the structural identity of the macrocyclic peptide lactam and the imide analog, a major side reaction product when allyl ester was used to protect the side chain of aspartic acid. A straightforward protocol modification was developed to minimize aspartimide formation during the synthesis of cyclic peptides.
Bioorganic & Medicinal Chemistry Letters 03/2005; 15(4):1065-8. · 2.55 Impact Factor
