title: Interaction of tachykinins with their receptors studied with cyclic analogues of substance P and neurokinin B.
abstract: 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 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 alpha-helix present substantial potencies. [Cys3,6]SP is as active as SP in inhibiting 125I-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, [Cys3,6]SP is as potent as neurokinin B in inhibiting 125I-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, [Cys3,6]SP is a weak agonist of the neurokinin 2 receptor subtype, as evidenced by its binding potency in inhibiting 3H-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 [Cys3,6]SP positions 8 and 9 were modified. [Cys3,6, Tyr8, Ala9]SP is slightly less selective than SP for the neurokinin 1 receptor subtype. [Cys2,5]neurokinin B constitutes a selective cyclic agonist for the neurokinin 3 receptor. The very weak potencies of the peptides from group II indicate that a certain degree of flexibility in the C-terminal moiety is required. 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.
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001923:Brain Chemistry; D004285:Dogs; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism; D008297:Male; D008968:Molecular Conformation; D015287:Neurokinin B; D009479:Neuropeptides / Q000031:analogs & derivatives / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter / Q000145:classification / Q000378:metabolism*; D018039:Receptors, Tachykinin; D013373:Substance P / Q000031:analogs & derivatives / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D009479:Neuropeptides; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; D013373:Substance P; D015287:Neurokinin B