کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2007017 1066361 2009 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Novel kinin B1 receptor agonists with improved pharmacological profiles
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
پیش نمایش صفحه اول مقاله
Novel kinin B1 receptor agonists with improved pharmacological profiles
چکیده انگلیسی

There is some evidence to suggest that inducible kinin B1 receptors (B1R) may play beneficial and protecting roles in cardiovascular-related pathologies such as hypertension, diabetes, and ischemic organ diseases. Peptide B1R agonists bearing optimized pharmacological features (high potency, selectivity and stability toward proteolysis) hold promise as valuable therapeutic agents in the treatment of these diseases. In the present study, we used solid-phase methodology to synthesize a series of novel peptide analogues based on the sequence of Sar[dPhe8]desArg9-bradykinin, a relatively stable peptide agonist with moderate affinity for the human B1R. We evaluated the pharmacological properties of these peptides using (1) in vitro competitive binding experiments on recombinant human B1R and B2R (for index of selectivity determination) in transiently transfected human embryonic kidney 293 cells (HEK-293T cells), (2) ex vivo vasomotor assays on isolated human umbilical veins expressing endogenous human B1R, and (3) in vivo blood pressure tests using anesthetized lipopolysaccharide-immunostimulated rabbits. Key chemical modifications at the N-terminus, the positions 3 and 5 on Sar[dPhe8]desArg9-bradykinin led to potent analogues. For example, peptides 18 (SarLys[Hyp3,Cha5, dPhe8]desArg9-bradykinin) and 20 (SarLys[Hyp3,Igl5, dPhe8]desArg9-bradykinin) outperformed the parental molecule in terms of affinity, functional potency and duration of action in vitro and in vivo. These selective agonists should be valuable in future animal and human studies to investigate the potential benefits of B1R activation.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Peptides - Volume 30, Issue 4, April 2009, Pages 788–795
نویسندگان
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