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Highly selective agonists for substance P receptor subtypes.

U Wormser, R Laufer, Y Hart

    The EMBO Journal
    |November 1, 1986
    PubMed
    Summary
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    Researchers identified a novel third tachykinin receptor, SP-N, in the mammalian nervous system using highly selective agonists. This discovery reveals distinct physiological functions for tachykinin receptors.

    Area of Science:

    • Neuroscience
    • Pharmacology
    • Molecular Biology

    Background:

    • Tachykinins are a family of peptide neurotransmitters involved in various physiological processes.
    • The existence and specific roles of different tachykinin receptors, including SP-N, remained incompletely understood.
    • Understanding receptor subtypes is crucial for developing targeted therapeutics.

    Purpose of the Study:

    • To demonstrate the existence of a third tachykinin receptor, designated SP-N, in the mammalian nervous system.
    • To characterize the selectivity and potency of novel agonists targeting tachykinin receptor subtypes.
    • To investigate the functional interactions between SP-N receptors and other signaling pathways.

    Main Methods:

    • Systematic N-methylation of substance P analogs to create selective agonists.

    Related Experiment Videos

  • Assessing receptor activation using guinea pig ileum contraction assays.
  • Determining the concentration-dependent effects of agonists on different tachykinin receptor subtypes (SP-N, SP-P, SP-E).
  • Investigating the effects of opioid peptides on SP-N receptor-mediated responses.

    • Main Results:

    • Development of highly selective agonists for the neuronal SP-N receptor.
    • Succinyl-[Asp6,Me-Phe8]SP6-11 demonstrated potent and selective activation of the SP-N receptor (EC50 = 0.5 nM).
    • SP-N agonists required >60,000-fold higher concentrations to activate SP-P and SP-E receptors.
    • Opioid peptides antagonized the action of selective SP-N agonists in the guinea pig ileum.

    Conclusions:

    • The study provides clear evidence for a distinct third tachykinin receptor, SP-N.
    • Selective agonists confirm the unique pharmacological profiles of tachykinin receptor subtypes.
    • Functional antagonism by opioids suggests a counterregulatory role between opiate and SP-N receptor systems.
    • These findings indicate that distinct tachykinin receptors mediate diverse physiological functions.