A potent and long-acting NK-1 selective agonist

Area of Science:

• Neuropharmacology
• Peptide research

Background:

• Substance P (SP) is a neuropeptide involved in various physiological processes.
• SP's effects are often limited by rapid degradation by peptidases.
• NK-1 receptors mediate many of SP's actions.

Purpose of the Study:

• To investigate the effects of SP and a selective NK-1 receptor agonist in vivo.
• To evaluate the impact of peptidase inhibitors on SP's actions.
• To assess the utility of a stable NK-1 agonist as a research tool.

Main Methods:

• Administration of SP and a selective NK-1 receptor agonist (Ac[Arg6,Sar9,Met(O2)11]SP(6-11)) to urethane-anesthetized rats.
• Co-administration of SP with a mixture of peptidase inhibitors (captopril, thiorphan, phosphoramidon).
• Measurement of hypotensive and sialologic (salivary secretion) effects.

Main Results:

• SP induced short-lasting hypotension and salivation.
• Peptidase inhibitors significantly potentiated and prolonged SP's effects (5-10 fold).
• The NK-1 agonist Ac[Arg6,Sar9,Met(O2)11]SP(6-11) demonstrated potent, prolonged hypotensive and sialologic effects, unaffected by peptidase inhibitors.

Conclusions:

• Peptidase inhibition enhances the in vivo activity of Substance P.
• Ac[Arg6,Sar9,Met(O2)11]SP(6-11) is a potent and stable NK-1 receptor agonist.
• This stable agonist is a valuable tool for studying NK-1 receptor functions in vivo.