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Updated: Jul 28, 2026
11:44
Synthesis and Structure Determination of µ-Conotoxin PIIIA Isomers with Different Disulfide Connectivities
Published on: October 2, 2018
Conformation-based design of two cyclic physalaemin analogues.
G Hölzemann1, A Jonczyk, V Eiermann
1Medicinal Chemistry Department, University of Sherbrooke, Canada.
Biopolymers
|May 1, 1991
Summary
Two novel cyclic physalaemin analogues were synthesized and tested. Charged side chains are not essential for NK-1 receptor activation, offering insights into neurokinin receptor interactions.
Area of Science:
- Medicinal Chemistry
- Peptide Chemistry
- Neuropharmacology
Background:
- Physalaemin is a tachykinin peptide with biological activity.
- Understanding the structure-activity relationship of physalaemin is crucial for drug design.
- Cyclic analogues can offer conformational stability and altered pharmacological profiles.
Purpose of the Study:
- To design and synthesize novel cyclic analogues of physalaemin.
- To investigate the conformational properties of these analogues.
- To evaluate their potency at neurokinin receptors, particularly NK-1.
Main Methods:
- Design based on solution conformation.
- Chemical synthesis of cyclic peptides (Glp-Ala-cyclo(-Asp-Pro-Asn-Lys-)-Phe-Tyr-Gly-Leu-Met-NH2 and a Glu-analogue).
- Nuclear Magnetic Resonance (NMR) spectroscopy for structural elucidation.
- Molecular dynamics simulations using Nuclear Overhauser Effect (NOE) data.
Main Results:
- Analogue 1 exhibited a conformation similar to physalaemin.
- Analogue 2, with a Glu replacement, did not form intramolecular hydrogen bonds.
- Both analogues showed similar potency to physalaemin at the dog carotid artery (NK-1 receptor).
- Cyclic peptides demonstrated sensitivity to other tachykinin receptors.
Conclusions:
- Charged side chains of physalaemin are not essential for NK-1 receptor activation.
- Cyclic analogues can provide insights into the biological significance of charged side chains in neurokinins.
- Modification of salt bridges to amide bonds can modulate receptor interactions.
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