FR 113680: a novel tripeptide substance P antagonist with NK1 receptor selectivity.
1. We have discovered a novel tripeptide substance P (SP) antagonist, FR 113680 [N alpha-[N alpha-(N alpha-acetyl-L-threonyl)-N'-formyl-D- tryptophyl]-N-methyl-N-phenylmethyl-L-phenylalaninamide]. In binding experiments, FR 113680 inhibited [3H]-SP binding to guinea-pig lung membranes (NK1) in a competitive manner but had not effect on [3H]-SP binding to rat cerebral cortical membranes (NK1), [3H]-neurokinin A ([3H]-NKA) binding to rat duodenum smooth muscle membranes (NK2) and [3H]-eledoisin (Ele) binding to rat cerebral cortical membranes (NK3). 2. In bioassay experiments, FR 113680 dose-dependently inhibited SP-induced guinea-pig ileum contraction (NK1), but did not inhibit either NKA-induced rat vas deferens contraction (NK2) or neurokinin B (NKB)-induced contraction of rat portal vein (NK3). According to Schild plot analysis, the inhibitory effect of FR 113680 on SP-induced guinea-pig ileum contraction is competitive and the pA2 value is 7.53. 3. The inactivity of FR 113680 on NK1 receptors in rat compared to guinea-pig may represent species-specific forms of the NK1 receptor. 4. These findings suggest that FR 113680 interacts selectively with the NK1 neurokinin receptor.
Morimoto
H
H
Department of Pharmacology, Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan.
Murai
M
M
Maeda
Y
Y
Hagiwara
D
D
Miyake
H
H
Matsuo
M
M
Fujii
T
T
D000818:Animals; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D008168:Lung / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000187:drug effects* / Q000378:metabolism; D018039:Receptors, Tachykinin; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D013570:Synaptic Membranes / Q000378:metabolism; D015320:Tachykinins / Q000378:metabolism / Q000494:pharmacology*; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
D009842:Oligopeptides; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; D015320:Tachykinins; C076202:FR 113680; D013373:Substance P