Importance of the leucine side-chain to the spasmogenic activity and binding of substance P analogues.
Previous studies with Substance P (SP) antagonists (GR 71251, [DPro9, Pro10, Trp11]SP and [DPro9, MeLeu10, Trp11]SP) have suggested the existence in the guinea-pig ileum (GPI) of two distinct tachykinin receptors associated with the contractile responses of [Pro9]SP and septide. In addition [Apa9-10]SP, a glycine-substituted analogue of SP with a carba bond between residues 9 and 10, [Gly9-psi(CH2-CH2)-Gly10]SP = [Apa9-10]SP, was shown to belong to the 'septide family' (low affinity for NK-1 specific binding sites and high potency in the GPI). In order to establish the importance of the isopropyl side-chain in position 10, the binding potencies and activities of [Gly9-psi(CH2-CH2)-Gly10]SP, [Ala10]SP, [Gly9-psi(CH2-CH2)-Leu10]SP and [Gly9-psi(CH2-CH2)-DLeu10]SP were compared. Conformational behaviour of active peptides with a carba bond was analyzed by NMR and modelisation studies. This study with agonists demonstrated that undecapeptides substituted in position 10 in the SP sequence also enabled discrimination of NK-1 receptors from receptors responsible for the spasmogenic activities of peptides belonging to the 'septide family'. [Gly9-psi(CH2-CH2)-Leu10]SP is a highly potent NK-1 agonist, [Gly9-psi(CH2-CH2)-Gly10]SP acts on the septide-sensitive receptor, and [Ala10]SP is a mixed agonist.
Lavielle
S
S
Laboratory of Biological Organic Chemistry, URA CNRS 493, Paris VI University, France.
Chassaing
G
G
Brunissen
A
A
Rodriguez
M
M
Martinez
J
J
Convert
O
O
Carruette
A
A
Garret
C
C
Petitet
F
F
Saffroy
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007930:Leucine / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008956:Models, Chemical; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011487:Protein Conformation; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives*
D010455:Peptides; D018039:Receptors, Tachykinin; D013373:Substance P; D007930:Leucine