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

Journal Article · Sun Nov 01 00:00:00 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), Vol. 84:22
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES
KININS
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PEPTIDES
MOLECULAR STRUCTURE
RECEPTORS
BRAIN
DOGS
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INTESTINES
IODINE 125
RATS
TRITIUM COMPOUNDS
ANIMALS
BETA DECAY RADIOISOTOPES
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GASTROINTESTINAL TRACT
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MAMMALS
MEMBRANE PROTEINS
NERVOUS SYSTEM
NUCLEI
ODD-EVEN NUCLEI
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ORGANS
POLYMERIZATION
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550201* - Biochemistry- Tracer Techniques