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Substance P--structure-activity studies and the development of antagonists
Pharmacology
|January 1, 1984
Summary
Researchers developed novel substance P (SP) antagonists by modifying peptide sequences. These new compounds show selectivity and aid in characterizing SP receptors in smooth muscles, suggesting multiple receptor types mediate SP effects.
Area of Science:
- Pharmacology
- Medicinal Chemistry
- Neuroscience
Background:
- Substance P (SP) and related peptides play crucial roles in various physiological processes.
- Previous attempts to develop SP antagonists were largely unsuccessful.
- Understanding SP's mechanism of action requires effective receptor antagonists.
Purpose of the Study:
- To design and synthesize novel peptide antagonists targeting substance P (SP) and related peptides.
- To investigate the structure-activity relationships of these antagonists.
- To characterize SP receptors in smooth muscles using the developed antagonists.
Main Methods:
- Modification of SP C-terminal partial sequences to create hexa-, octa-, and undecapeptide antagonists.
- Systematic substitutions of natural amino acid residues with tryptophan (trp) to enhance affinity and selectivity.
- Evaluation of antagonist potency and selectivity in various isolated smooth muscle preparations (rabbit mesenteric vein, guinea pig ileum, guinea pig trachea, dog carotid artery).
Main Results:
- Single modifications (e.g., Leu10 to trp) yielded weak antagonists.
- Multiple substitutions (trp at positions 7, 9, and 10) significantly increased antagonist affinity.
- Specific octapeptide antagonists ([pro4, trp7,9, Nle11]-SP(4-11) and [pro4, trp7,9,10,Phe11]-SP(4-11)) demonstrated potent and selective inhibition of SP activity in different tissues.
- Undecapeptide antagonists showed complex behavior, including initial agonistic effects, but ultimately served as potent antagonists, particularly against kasinin and eledoisin.
Conclusions:
- Novel octa- and undecapeptide antagonists of substance P were successfully developed through targeted amino acid substitutions.
- These antagonists exhibit varying degrees of potency and selectivity across different smooth muscle tissues, aiding in SP receptor characterization.
- The findings suggest the existence of multiple receptor types mediating the diverse pharmacological effects of SP and related peptides.