Subtype- and species-selectivity of a tachykinin receptor antagonist, FK888, for cloned rat and human tachykinin receptors

doi:10.1016/0922-4106(94)90098-1

European Journal of Pharmacology: Molecular Pharmacology

Volume 269, Issue 2, 14 October 1994, Pages 277-281

https://doi.org/10.1016/0922-4106(94)90098-1 Get rights and content

Abstract

We investigated the receptor-binding properties and potencies of FK888 (N²-[(4R)]-4-hydroxy-1-(1-methyl-1H-indol-3-yl) carbonyl-L-prolyl]-N-methyl-N-phenylmethyl-3-(2-naphthyl)-L-alaninamide), a tachykinin receptor antagonist, for the rat and human tachykinin receptor subtypes (NK₁, NK₂ and NK₃) expressed in transfected mammalian cells. In displacement analyses, using membrane preparations derived from monkey kidney COS-7 cells transiently expressing tachykinin receptor subtypes, FK888 showed a subtype selectivity for NK₁ receptor and its affinity for the human NK₁ receptor was 320-fold higher than that for the rat NK₁ receptor, demonstrating species difference in its binding affinity. This was in marked contrast to FK224 (N-[N²- [N-[N-[N-[2,3-didehydro-N-methyl-N-[N-[3-(2-pentylphenyl)- propionyl]-L-threonyl]tyrosyl-L-leucynyl]-D-phenylalanyl]-L- allo- threonyl]-L-asparaginyl]-L-serine-n-lactone) that was selective for NK₁ and NK₂ receptors with similar affinities for the rat and human receptors. In Chinese hamster ovary cells permanently expressing the human NK₁ receptor, FK888 inhibited the substance P-induced phosphatidylinositol hydrolysis and produced a parallel shift in the dose-response curve for substance P. Schild analysis of the antagonism of phosphatidylinositol hydrolysis by FK888 yielded a pA₂ value of 8.9 and a slope of 0.97 of the regression line. FK888 itself showed no stimulatory effect on phosphatidylinositol hydrolysis in Chinese hamster ovary cells expressing the human NK₁ receptor. Thus, FK888 is a potent, competitive and selective antagonist for human NK₁ receptor.

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2011, Neuroscience Letters
Tachykinin NK-2 receptor, a cognate receptor for neurokinin A, expressed in the brain has been suggested as a new target for the treatment of psychiatric disorders. In rodents, treatment with NK-2 receptor agonists causes anxiogenic effects, while NK-2 receptor antagonists show anxiolytic and antidepressant-like effects. However, information about the distribution and functions of NK-2 receptors in the central nervous system (CNS) in primates is still lacking. Here, we examined the distribution and pharmacological profile of NK-2 receptors in the rhesus monkey (Macaca mulatta) to clarify the molecular basis of NK-2-mediated tachykininergic functions in the primate CNS. NK-2 receptors cloned from the rhesus monkey brain showed similar pharmacological properties to those of human NK-2 receptors. Substantial expression levels of NK-2 mRNA were observed in all the brain regions examined, including areas pertinent to the emotional networks such as the prefrontal cortex, cingulate cortex and amygdala. These findings suggest that NK-2 receptors may play important roles in the pathophysiology of psychiatric disorders.
Inflammatory pain in the rabbit: A new, efficient method for measuring mechanical hyperalgesia in the hind paw
2008, Journal of Neuroscience Methods
The discovery of novel analgesic compounds that target some receptors can be challenging due to species differences in ligand pharmacology. If a putative analgesic compound has markedly lower affinity for rodent versus other mammalian orthologs of a receptor, the evaluation of antinociceptive efficacy in non-rodent species becomes necessary. Here, we describe a new, efficient method for measuring inflammation-associated nociception in conscious rabbits. An electronic von Frey device is used, consisting of a rigid plastic tip connected to a force transducer in a hand-held probe. The plastic tip is applied to the plantar surface of a hind paw with increasing force until a withdrawal response is observed. The maximum force (g) tolerated by the rabbit (i.e., withdrawal threshold) is recorded. In young, conscious rabbits (500–700 g), baseline hind paw withdrawal thresholds typically fell within the 60–80 g range. Three hours after injection of the inflammatory agent carrageenan (3%, 200 μL, intra-plantar), withdrawal thresholds dropped by ∼30–40 g, indicating the presence of punctate mechanical hyperalgesia. The development of hyperalgesia was dose dependently prevented by the NSAID indomethacin (ED₅₀ = 2.56 mg/kg, p.o.) or the bradykinin B₂ receptor peptide antagonist HOE 140 (intra-paw administration). An established hyperalgesia was dose dependently reversed by morphine sulfate (ED₅₀ = 0.096 mg/kg, s.c.) or the bradykinin B₁ receptor peptide antagonist [des-Arg¹⁰,Leu⁹]-kallidin (ED₅₀ = 0.45 mg/kg, s.c.). Rabbits treated with the novel B₁ receptor small molecule antagonist compound A also showed dose-dependent reversal of hyperalgesia (ED₅₀ = 20.19 mg/kg, s.c.) and analysis of plasma samples taken from these rabbits showed that, unlike other rabbit pain models, the current method permits the evaluation of pharmacokinetic–pharmacodynamic (PK–PD) relationships (compound A plasma EC₅₀ = 402.6 nM). We conclude that the Electrovonfrey^® method can be used in rabbits with inflammatory pain to generate reliable dose- and plasma concentration-effect curves for different classes of analgesics.
Involvement of substance P in scratching behaviour in an atopic dermatitis model
2004, European Journal of Pharmacology
Substance P is speculated to be a key mediator of itching in atopic dermatitis, possibly acting via the tachykinin NK₁ receptor. Thus, we examined the effect of a tachykinin NK₁ antagonist, BIIF 1149 CL, on scratching behaviour in a picrylchloride-induced dermatitis model in NC/Nga mice. BIIF 1149 CL ((S)-N-[2-[3,5-bis(trifluoromethyl) phenyl]ethyl]-4-(cyclopropylmethyl)-N-methyl-α-phenyl-1-piperazineacetamide, monohydrochloride, monohydrate) at a dose of 100 mg/kg, p.o., significantly inhibited scratching behaviour immediately after administration, and the effect continued up to 6 h. The results suggest that clinical trials of tachykinin NK₁ antagonists for the treatment of itching in atopic dermatitis patients would be warranted.
Contribution of tachykinin receptor subtypes to micturition reflex in guinea pigs
2003, European Journal of Pharmacology
The aim of the present study was to determine the role of tachykinin in the micturition reflex in guinea pigs. We investigated the effects of tachykinin NK₁ receptor antagonists, GR205171 ([2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-(2S-phenyl-piperidin-3S-yl)-amine), CP99994 ((+), (2R, 3R)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine) and FK888 (N²-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl) carbonyl-l-prolyl]-N-methyl-N-phenylmethyl-3-(2-naphthyl)-l-alaninamide), the tachykinin NK₂ receptor antagonist, SR48968 ((+)-N-methyl-[4-(4-acetylamino-4-phenyl piperidino)-2-(3, 4-dichloro-phenyl)butyl] benzamide), and the tachykinin NK₃ receptor antagonist, SB223412 ((S)-(−)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide) on rhythmic bladder contraction. GR205171 and CP99994 but not SR48968 or SB223412 reduced bladder contraction frequency. FK888 inhibited the frequency very slightly at the highest dose tested. The distribution of tachykinin NK₁ receptor antagonists to the central nervous system after intravenous administration was examined using an ex vivo binding assay. GR205171 was distributed to the brain and spinal cord, but the tachykinin NK₁ receptor antagonist, FK888, was not. These results suggest that tachykinin NK₁ receptors, which are located in the central nervous system, play an important role in micturition in guinea pigs.
Unique gradual and sustained vasodilator response to substance P in the rabbit knee joint
2000, European Journal of Pharmacology
The effects of substance P on blood flow, plasma extravasation, and knee joint sizes in the rabbit were investigated. Topical bolus application of substance P (1 nmol) onto the exposed rabbit knee joint capsule increased its blood flow from 15 min onwards and reached a peak of 46% at 90 min compared to saline administration. However, administration by the same route and the same dose of the NK₁ receptor agonist [Sar⁹, Met (O₂)¹¹]substance P produced no change on the knee joint blood flow compared to the saline control. The NK₁ receptor antagonist N²-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-l-prolyl]-N-methyl-N-phenylmethyl-3-(2-naphthyl)-l-alaninamide (FK888) and the NK₂ receptor antagonist (S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-butyl] benzamide (SR48968), at 2×1 nmol and 2×10 nmol, had no effect on the substance P-induced response, which however was reduced by pyrilamine, cimetidine, and flurbiprofen (all at 2×10 nmol). N^G-nitro-l-arginine methyl ester (l-NAME) and N^G-nitro-d-arginine methyl ester (d-NAME), both at 2×100 nmol, did not significantly affect the substance P-induced response. Unilateral intra-articular administration of substance P (1 nmol) into synovial cavities of the rabbit knee joint increased basal blood flow of the ipsilateral joint at 4 h post-injection, and bilateral increase of basal blood flow was observed at 24 h. Plasma extravasation was significantly higher in the substance P-injected knee compared to the contralateral saline-injected knee at 4 h after intra-articular administrations, but not at 24 h. Knee joint sizes were not affected at both time points. The present study is the first to demonstrate that substance P possesses a gradual and persistent vasorelaxant action in the rabbit knee joint. This novel action of substance P is not mediated by NK₁ or NK₂ receptors, but involves histamine and prostaglandins. The degree of plasma extravasation elicited by substance P in the rabbit knee joint is small and short-lived, and with no concurrent oedema of the joint. These results suggest that substance P can evoke acute inflammatory responses in the rabbit knee joint, but on its own, it is unlikely to cause chronic joint inflammation in this species.
Analysis of the inflammatory response induced by substance P in the mouse pleural cavity
1999, Peptides
This study analyzes both cell migration and exudation responses elicited by substance P (SP) in the mouse pleural cavity. SP caused, 4 h after its administration into the mouse pleural cavity, a dose-related recruitment of leukocytes (ED₅₀ = 14.2 nmol), mainly due to mononuclears. Leukocytes peaked between 2 and 4 h, being followed by a slight decay that remained elevated for up to 24 h. Exudation, although small, was significantly elevated from 2 to 96 h after. NK₁ (FK 888) or NK₃ (SR 142801), but not NK₂ (SR 48968) tachykinin receptor antagonists, significantly inhibited cell migration. HOE 140 and NPC 17731, bradykinin B₂ receptor antagonists, caused graded inhibition of cell influx (ID₅₀s of 0.03 and 0.04 pmol), but des-Arg⁹-Leu⁸-BK, B₁ receptor antagonist, had no effect. The nitric oxide inhibitors l-NOARG and l-NAME, but not d-NAME, significantly inhibited SP-induced pleurisy. Pretreatment of the animals with indomethacin, dexamethasone, terfenadine, theophylline or salbutamol produced significant inhibition of the inflammatory parameters, whereas cromolyn only inhibited exudation. These results indicate that intrapleural injection of SP in mice elicit a long-lasting inflammatory reaction that is characterized by the participation of nitric oxide, kinins, cyclooxygenase metabolites and histamine. Antiasthmatic drugs such as theophylline, salbutamol, dexamethasone, and, to a lesser extent cromolyn, also markedly inhibit this inflammatory reaction. These results provide clear evidence supporting the role played by SP in neurogenic inflammation.

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Short communicationSubtype- and species-selectivity of a tachykinin receptor antagonist, FK888, for cloned rat and human tachykinin receptors

Abstract

Lancet

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Trends Pharmacol. Sci.

J. Biol. Chem.

J. Biol. Chem.

Trends Pharmacol. Sci.

Short communication
Subtype- and species-selectivity of a tachykinin receptor antagonist, FK888, for cloned rat and human tachykinin receptors