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Synthesis, biological activity, and conformational analysis of [pGlu6,N-MePhe8,Aib9] substance P (6-11): a selective agonist for the NK-3 receptor.
- Source :
-
Biopolymers [Biopolymers] 1993 Jun; Vol. 33 (6), pp. 915-26. - Publication Year :
- 1993
-
Abstract
- A highly potent and selective agonist to the tachykinin NK-3 receptor, [pGlu6,N-MePhe8,Aib9] substance P (6-11) (I), was synthesized via the solid phase method. The ED50 of I was 4 nM in the guinea pig ileum in the absence of atropine (NK-1+NK-3 receptors) and this agonist was 5000-fold less potent in the presence of atropine (NK-1 receptor). The analogue was virtually inactive in the rat vas deferens (NK-2 receptor). A detailed analysis of the solution conformation of this analogue in DMSO-d6 and in a DMSO-d6/H2O cryomixture was carried out by a combination of 1H-nmr 2D techniques (DQF-COSY, TOCSY, NOESY and ROESY) and model building based on empirical energy calculations. Peptide I exists as a mixture of isomers containing cis and trans Phe-N-MePhe peptide bonds. The main isomer, containing a cis Phe-N-MePhe peptide bond, shows a preferred folded conformation characterized by a type VI beta-turn with Phe and N-MePhe in the i + 1 and i + 2 positions. The turn is followed by a helical segment extending to the C-terminal. This conformation is compared to previously reported conformations of other selective tachykinin agonists and may be a promising lead for the design of novel NK-3 agonists with additional conformational constraints.
- Subjects :
- Amino Acid Sequence
Animals
Guinea Pigs
In Vitro Techniques
Male
Molecular Sequence Data
Peptide Fragments chemical synthesis
Peptide Fragments pharmacology
Protein Conformation
Pyrrolidonecarboxylic Acid analogs & derivatives
Rats
Receptors, Tachykinin
Substance P chemical synthesis
Substance P chemistry
Substance P pharmacology
Peptide Fragments chemistry
Receptors, Neurotransmitter physiology
Substance P analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 0006-3525
- Volume :
- 33
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Biopolymers
- Publication Type :
- Academic Journal
- Accession number :
- 7686410
- Full Text :
- https://doi.org/10.1002/bip.360330607