Influence of the replacement of amino acid by its D-enantiomer in the sequence of substance P. 1. Binding and pharmacological data.
The D-enantiomer of residues 2, 4, 5, 6, 7, 8, 10 and 11 was introduced in the sequence of Substance P: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2. The achiral glycine residue was replaced by a D-Ala residue. Regarding NK-1 binding potencies or activities, changing to the D-enantiomer in positions 2, 4 or 5 did not modify the pharmacological patterns of the resulting peptides. Introduction of a D-residue in the 6 to 11 sequence drastically decreased the potency of the D-analogues with the exception of [D-Leu10]SP which was found only three times less potent than SP in contracting the guinea-pig ileum. No clear cut evidence between the binding potencies and activities on NK-1, NK-2 and NK-3 assays, was observed which allows a more rational design of tachykinins antagonists.
Duplaa
H
H
Laboratoire de Chimie Organique Biologique, CNRS URA 493, Université Paris VI, France.
Chassaing
G
G
Lavielle
S
S
Beaujouan
J C
JC
Torrens
Y
Y
Saffroy
M
M
Glowinski
J
J
D'Orléans Juste
P
P
Regoli
D
D
Carruette
A
A
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002339:Carotid Arteries; D002540:Cerebral Cortex / Q000378:metabolism; D004285:Dogs; D004386:Duodenum; D006168:Guinea Pigs; D007082:Ileum; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D018039:Receptors, Tachykinin; D013237:Stereoisomerism; D013373:Substance P / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013574:Synaptosomes / Q000378:metabolism; D015320:Tachykinins
D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; D015320:Tachykinins; D013373:Substance P