Design, Synthesis and Pharmacological Characterization of a Potent Radioiodinated and Photoactivatable Peptidic Oxytocin Antagonist

Using a segment strategy, we have synthesized four iodinated photoactivatable cyclic peptidic ligands of oxytocin, bearing a β-mercapto-ββ-cyclopentamethylene propionic group (Pmp) on their N-terminus. All the syntheses were RP-HPLC monitored, and the compounds were HPLC purified. They were characte...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2001-08, Vol.44 (18), p.3022-3030
Main Authors: Carnazzi, Eric, Aumelas, André, Mouillac, Bernard, Breton, Christophe, Guillou, Laurent, Barberis, Claude, Seyer, René
Format: Article
Language:English
Subjects:
Animals
Binding, Competitive
Biological and medical sciences
CHO Cells
Chromatography, High Pressure Liquid
Cricetinae
Drug Design
Hormones. Endocrine system
Humans
In Vitro Techniques
Inositol Phosphates - biosynthesis
Iodine Radioisotopes
Magnetic Resonance Spectroscopy
Medical sciences
Peptides, Cyclic - chemical synthesis
Peptides, Cyclic - chemistry
Peptides, Cyclic - pharmacology
Pharmacology. Drug treatments
Photolysis
Radioligand Assay
Receptors, Oxytocin - antagonists & inhibitors
Spectrometry, Mass, Fast Atom Bombardment
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Structure-Activity Relationship
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Summary:Using a segment strategy, we have synthesized four iodinated photoactivatable cyclic peptidic ligands of oxytocin, bearing a β-mercapto-ββ-cyclopentamethylene propionic group (Pmp) on their N-terminus. All the syntheses were RP-HPLC monitored, and the compounds were HPLC purified. They were characterized by 1H NMR, MALDI-TOF, or FAB mass spectrometries. The affinities of Pmp-Tyr(Me)-Ile-Thr-Asn-Cys-Gly-Orn-Phe(3I,4N3)-NH2 (20), Pmp-Tyr-Ile-Thr-Asn-Cys-Gly-Orn-Phe(3I,4N3)-NH2 (21), Pmp-Tyr(Me)-Ile-Thr-Asn-Cys-Pro-Orn-Phe(3I,4N3)-NH2 (22), and Pmp-Tyr-Ile-Thr-Asn-Cys-Pro-Orn-Phe(3I,4N3)-NH2 (23) were evaluated as inhibition constants (K i, in nM) for the human oxytocin receptor expressed in Chinese hamster ovary cells by displacement of a radioiodinated disulfide-cyclized antagonist (Elands et al. Eur. J. Pharmacol. 1987, 147, 197−207). The most potent of them, compound 22, was synthesized by another method in order to allow its radiolabeling by 125I. Its dissociation constant (K d) for the human oxytocin receptor, directly measured in saturation studies, was 0.25 ± 0.04 nM, and its antagonist properties were determined by inactivation of phospholipase C, thus obtaining an inactivation constant (K inact) of 0.18 ± 0.02 nM, evaluated by inositol phosphate accumulation. This compound is a very good tool for the mapping of peptidic antagonist binding sites in the human oxytocin receptor.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm010125u