Interaction of tachykinins with their receptors studied with cyclic analogues of substance P and neurokinin B

Journal Article · Sun Nov 01 04:00:00 EST 1987 · Proc. Natl. Acad. Sci. U.S.A.; (United States)

DOI:https://doi.org/10.1073/pnas.84.22.8095· OSTI ID:6618733

Ploux, O; Lavielle, S; Chassaing, G; Julien, S; Marquet, A; D'Orleans-Juste, P; Dion, S; Regoli, D; Beaujouan, J C; Bergstroem, L

The activities of two groups of cyclic agonists of substance P (SP) have been studied. The disulfide bridge constraints have been designed on the basis of conformational studies on SP and physalaemin indicating an ..cap alpha..-helical structure for the core of these two tachykinins (group I) and a folding of the C-terminal carboxamide towards the side chains of the glutamines 5 and 6 (group II). Only peptides simulating the ..cap alpha..-helix present substantial potencies. (Cys/sup 3,6/)SP is as active as SP in inhibiting /sup 125/I-labeled Bolton and Hunter SP-specific binding on rat brain synaptosomes and on dog carotid bioassay, two assays specific for the neurokinin 1 receptor. Moreover, (Cys/sup 3,6/)SP is a potent as neurokinin B in inhibiting /sup 125/I-labeled Bolton and Hunter eledoisin-specific binding on rat cortical synaptosomes as well as in stimulating rat portal vein, two tests specific for the neurokinin 3 receptor. Interestingly, in contrast to neurokinin B, (Cys/sup 3,6/)SP is a weak agonist of the neurokinin 2 receptor subtype, as evidenced by its binding potency in inhibiting /sup 3/H-labeled neurokinin A-specific binding on rat duodenum and in inducing the contractions of the rabbit pulmonary artery, a neurokinin 2-type bioassay. To increase the specificity of the cyclic analogue (Cys/sup 3,6/)SP positions 8 and 9 were modified. Collectively, these results suggest that the neurokinin 1 and neurokinin 3 tachykinin receptors may recognize a similar three-dimensional structure of the core of the tachykinins. Different orientations of the common C-terminal tripeptide may be related to the selectivity for the different receptor subtypes.

• Research Organization: Universite P. et M. Curie, Paris (France)
• OSTI ID: 6618733
• Journal Information: Proc. Natl. Acad. Sci. U.S.A.; (United States), Journal Name: Proc. Natl. Acad. Sci. U.S.A.; (United States) Vol. 84:22; ISSN PNASA
• Country of Publication: United States
• Language: English

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550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMALS
BETA DECAY RADIOISOTOPES
BODY
BRAIN
CENTRAL NERVOUS SYSTEM
CHEMICAL REACTIONS
CROSS-LINKING
DAYS LIVING RADIOISOTOPES
DIGESTIVE SYSTEM
DOGS
ELECTRON CAPTURE RADIOISOTOPES
GASTROINTESTINAL TRACT
GUINEA PIGS
INTERMEDIATE MASS NUCLEI
INTESTINES
IODINE 125
IODINE ISOTOPES
ISOTOPES
KININS
LABELLED COMPOUNDS
MAMMALS
MEMBRANE PROTEINS
MOLECULAR STRUCTURE
NERVOUS SYSTEM
NUCLEI
ODD-EVEN NUCLEI
ORGANIC COMPOUNDS
ORGANS
PEPTIDES
POLYMERIZATION
POLYPEPTIDES
PROTEINS
RADIOISOTOPES
RATS
RECEPTORS
RODENTS
TRITIUM COMPOUNDS
VERTEBRATES