Modification of the potent peptide FK888 with unusual aminoacids: effects on activity on neurokinin receptors.
We report on the synthesis and the pharmacological properties of a new series of tachykinin antagonists based on the peptide N2-[(4R)-4-hydroxy-1-[(1-methyl-1H-indol-3-yl) carbonyl]-L-prolyl]-N-methyl-N-(phe-nylmethyl)-3-(2-naphthyl)-L-al aninamide (FK888) modified on the (2-naphthyl)-L-alanine and the [(1-methyl-1H-indol-3-yl)carbonyl] moieties. The compounds were tested on guinea pig ileum for NK-1, rat colon for NK-2 and rat portal vein for NK-3 receptors. The two most potent peptides of this series, 1b and 2b, were selective for the NK-2 receptor (pA2 = 7.5 and 7.3, respectively).
Caliendo
G
G
Dipartimento di Chimica Farmaceutica e Tossicologica, Università Federico II, Napoli, Italy.
Greco
G
G
Grieco
P
P
Perissutti
E
E
Santagada
V
V
Calignano
A
A
Mancuso
F
F
Novellino
E
E
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003106:Colon / Q000187:drug effects; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D016339:Spectrometry, Mass, Fast Atom Bombardment
D000596:Amino Acids; D004151:Dipeptides; D007211:Indoles; D064729:Neurokinin-1 Receptor Antagonists; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; C078949:FK 888