Highly potent substance P antagonists substituted with beta-phenyl- or beta-benzyl-proline at position 10.
In the guinea-pig ileum tissue, [Pro9]substance P, a tachykinin NK1 receptor selective agonist and septide, [pGlu6,Pro9]-substance P-(6-11), do not interact with the same receptor as shown by the different inhibitory profiles of GR 72251 and [D-Pro9,Pro10,Trp11]substance P. Substitution at position 10 of the D-Pro9-Pro10 moiety with bulky N-methylated amino acids increased the antagonist potency for the tachykinin NK1 receptor without affecting that for the 'septide-sensitive receptor'. The incorporation of a trans-beta-L-substituted proline in position 10, for example a benzyl group (beta-benzyl-L-proline), afforded a potent antagonist active in the nanomolar range. For GR 82334, this increase in potency was obtained at the expense of selectivity for tachykinin NK1 and 'septide-sensitive' receptors.
Lavielle
S
S
Laboratoire de Chimie Organique Biologique, CNRS URA 493, Université P. et M. Curie, Paris, France.
Brunissen
A
A
Carruette
A
A
Garret
C
C
Chassaing
G
G
D000595:Amino Acid Sequence; D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000494:pharmacology; D010803:Physalaemin / Q000031:analogs & derivatives / Q000494:pharmacology; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D011817:Rabbits; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology
D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; C067285:substance P, Pro(9)-; C079014:GR 82334; D010803:Physalaemin; D013373:Substance P; C054725:septide; D011761:Pyrrolidonecarboxylic Acid