GR159897, a potent non-peptide antagonist at tachykinin NK2 receptors

doi:10.1016/0014-2999(94)00655-Q

European Journal of Pharmacology

Volume 272, Issues 2–3, 16 January 1995, Pages 241-248

https://doi.org/10.1016/0014-2999(94)00655-Q Get rights and content

Abstract

GR159897 ((R)-1-[2-(5-fluoro-1H-indol-3-yl)ethyl]-4-methoxy-4-[(phenylsulfinyl)methyl]piperidine) is a novel, highly potent and selective non-peptide antagonist at tachykinin NK₂ receptors. GR159897 inhibited binding of the NK₂ receptor antagonist radioligand [³H]cyclohexylcarbonyl-Gly-Ala-(d)Trp-Phe-NMe₂ ([³H]GR100679) to human ileum NK₂ receptors transfected into Chinese hamster ovary cells (pK_i 9.5) and to rat colon membranes (pK_i 10.0). GR159897 was a competitive antagonist of contractions induced by the NK₂ receptor agonist [Lys³,Gly⁸-R-γ-lactam-Leu⁹]neurokinin A-(3–10) (GR64349) in guinea-pig trachea (pA₂ 8.7), and had negligible activity at human NK₁ receptors transfected into Chinese hamster ovary cells (pK_i 5.3), NK₁ receptors in guinea-pig trachea (pK_B < 5) or NK₃ receptors in guinea-pig cerebral cortex (pK_i < 5). In vivo, in the anaesthetised guinea-pig, GR159897 (0.12 mg · kg⁻¹ i.v.) potently antagonised bronchoconstriction induced by GR64349 (dose-ratio = 28), with a long duration of action (3 h). GR159897 should be a useful tool for studying the physiological and pathophysiological role of tachykinin NK₂ receptor activation.

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Cited by (42)

Regional differences of tachykinin effects on smooth muscle and pacemaker potentials of the stomach, duodenum, ileum and colon of an emetic model, the house musk shrews
2023, Neuropeptides
Citation Excerpt :
We also explored the potential role of NK2 receptors in mediating neuromuscular transmission. The pKi of both GR159,897 and SR48,968 is 9.5 (Anthes et al., 2002; Beresford et al., 1995). GR159,897 (10 μM) has been shown to significantly inhibit EFS-induced contractions of the stomach, ileum and colon, with, albeit insignificant, inhibitory trends in the duodenum.
The contractile effects of tachykinins on the gastrointestinal tract are well-known, but how they modulate slow-waves, particularly in species capable of emesis, remains largely unknown. We aimed to elucidate the effects of tachykinins on myoelectric and contractile activity of isolated gastrointestinal tissues of the Suncus murinus.
The effects of substance P (SP), neurokinin (NK)A, NKB and selective NK₁ (CP122,721, CP99,994), NK₂ (SR48,968, GR159,897) and NK₃ (SB218,795, SB222,200) receptor antagonists on isolated stomach, duodenum, ileum and colon segments were studied. Mechanical contractile activity was recorded using isometric force displacement transducers. Electrical pacemaker activity was recorded using a microelectrode array.
Compared with NKA, SP induced larger contractions in stomach tissue and smaller contractions in intestinal segments, where oscillation magnitudes increased in intestinal segments, but not the stomach. CP122,721 and GR159,897 inhibited electrical field stimulation-induced contractions of the stomach, ileum and colon. NKB and NK₃ had minor effects on contractile activity. The inhibitory potencies of SP and NKA on the peristaltic frequency of the colon and ileum, respectively, were correlated with those on electrical pacemaker frequency. SP, NKA and NKB inhibited pacemaker activity of the duodenum and ileum, but increased that of the stomach and colon. SP elicited a dose-dependent contradictive pacemaker frequency response in the colon.
This study revealed distinct effects of tachykinins on the mechanical and electrical properties of the stomach and colon vs. the proximal intestine, providing a unique aspect on neuromuscular correlation in terms of the effects of tachykinin on peristaltic and pacemaker activity in gastrointestinal-related symptoms.
Communication Between Enteric Neurons, Glia, and Nociceptors Underlies the Effects of Tachykinins on Neuroinflammation
2018, Cellular and Molecular Gastroenterology and Hepatology
Tachykinins are involved in physiological and pathophysiological mechanisms in the gastrointestinal tract. The major sources of tachykinins in the gut are intrinsic enteric neurons in the enteric nervous system and extrinsic nerve fibers from the dorsal root and vagal ganglia. Although tachykinins are important mediators in the enteric nervous system, how they contribute to neuroinflammation through effects on neurons and glia is not fully understood. Here, we tested the hypothesis that tachykinins contribute to enteric neuroinflammation through mechanisms that involve intercellular neuron-glia signaling.
We used immunohistochemistry and quantitative real-time polymerase chain reaction, and studied cellular activity using transient-receptor potential vanilloid-1 (TRPV1)^tm1^(cre)Bbm/J::Polr2a^{tm1(CAG-GCaMP5g,-tdTomato)Tvrd} and Sox10CreER^T2::Polr2a^{tm1(CAG-GCaMP5g,-tdTomato)Tvrd} mice or Fluo-4. We used the 2,4-di-nitrobenzene sulfonic acid (DNBS) model of colitis to study neuroinflammation, glial reactivity, and neurogenic contractility. We used Sox10::CreER^T2+/-/Rpl22^tm1.1Psam/J mice to selectively study glial transcriptional changes.
Tachykinins are expressed predominantly by intrinsic neuronal varicosities whereas neurokinin-2 receptors (NK2Rs) are expressed predominantly by enteric neurons and TRPV1-positive neuronal varicosities. Stimulation of NK2Rs drives responses in neuronal varicosities that are propagated to enteric glia and neurons. Antagonizing NK2R signaling enhanced recovery from colitis and prevented the development of reactive gliosis, neuroinflammation, and enhanced neuronal contractions. Inflammation drove changes in enteric glial gene expression and function, and antagonizing NK2R signaling mitigated these changes. Neurokinin A–induced neurodegeneration requires glial connexin-43 hemichannel activity.
Our results show that tachykinins drive enteric neuroinflammation through a multicellular cascade involving enteric neurons, TRPV1-positive neuronal varicosities, and enteric glia. Therapies targeting components of this pathway could broadly benefit the treatment of dysmotility and pain after acute inflammation in the intestine.
Substance P induces gastric mucosal protection at supraspinal level via increasing the level of endomorphin-2 in rats
2013, Brain Research Bulletin
Citation Excerpt :
No data have been published to our knowledge on the i.c.v. dose of L-733,060 and GR 159897 in rats, however a wide dose range (from picomolar to micromolar: Pacharinsak et al., 2008; Rittner et al., 2007; Walsh et al., 1995) was used in the case of other routes of administration. The applied doses in the present study (1 nmol for L-733,060 and 0.5 nmol for GR 159897) were based partly on our preliminary results, partly on the estimated affinity of these ligands for the NK1 and NK2 receptors, respectively, derived from in vitro studies (Beresford et al., 1995; Seabrook et al., 1996). The properties of EM-2 antiserum have been described previously in detail (Szemenyei et al., 2008).
The aim of the present study was to analyze the potential role of substance P (SP) in gastric mucosal defense and to clarify the receptors and mechanisms that may be involved in it. Gastric ulceration was induced by oral administration of acidified ethanol in male Wistar rats. Mucosal levels of calcitonin gene-related peptide (CGRP) and somatostatin were determined by radioimmunoassay. For analysis of gastric motor activity the rubber balloon method was used. We found that central (intracerebroventricular) injection of SP (9.3–74 pmol) dose-dependently inhibited the formation of ethanol-induced ulcers, while intravenously injected SP (0.37–7.4 nmol/kg) had no effect. The mucosal protective effect of SP was inhibited by pretreatment with neurokinin 1-, neurokinin 2-, neurokinin 3- and μ-opioid receptor antagonists, while δ- and κ-opioid receptor antagonists had no effect. Endomorphin-2 antiserum also antagonized the SP-induced mucosal protection. In the gastroprotective dose range SP failed to influence the gastric motor activity. Inhibition of muscarinic cholinergic receptors, or the synthesis of nitric oxide or prostaglandins significantly reduced the effect of SP. In addition, centrally injected SP reversed the ethanol-induced reduction of gastric mucosal CGRP content. It can be concluded, that SP may induce gastric mucosal protection initiated centrally. Its protective effect is likely to be mediated by endomorphin-2, and vagal nerve may convey the centrally initiated protection to the periphery, where both prostaglandins, nitric oxide and CGRP are involved in mediating this effect.
Role of tachykinin and neurokinin receptors in the regulation of ovine omasal contractions
2012, Regulatory Peptides
Citation Excerpt :
Water was freely available. We examined 1) the effects of SP, NKA and NKB application on basal tension of longitudinal and circular muscle strips of the greater curvature of the omasum, 2) the effects of NK-1R antagonist L-732,138 [20,21] and NK-2R antagonist GR159897 [22,23] on SP- and NKA-induced contractions, and 3) the effects of the NK-R antagonists application on EFS-induced contractions. Six sheep were used for the in vitro experiment of muscle contraction.
The present study investigated a role of tachykinins (TK) and neurokinin (NK) receptors (NK-R) in the non-cholinergic regulation of omasal contractions in sheep. Semiquantitative reverse transcription (RT)-PCR revealed that both preprotachykinin (PPT)-A and PPT-B mRNA were distributed in the omasal muscle layers and that NK-R type-1 (NK-1R) and type-2 (NK-2R) mRNA were largely expressed in the same tissues. Cumulative application of substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) at 0.03–10 μM induced tonic contractions of omasal muscle strips, and the contractile amplitude increased in order of NKB < SP ≪ NKA in longitudinal and circular muscle strips. Although cumulative application of NK-1R antagonist, L-732,138, at 1–100 μM did not significantly inhibit SP- and NKA-induced contractions in both muscle layers, NK-2R antagonist GR159897 at 30–100 μM significantly inhibited NKA-induced contraction of longitudinal muscles and showed tendency to inhibit that in circular muscles. Electric field stimulation (EFS)-induced contractions of omasal muscle strips, which were atropine-resistant, were significantly inhibited by GR159897 at 30 and 100 μM in both muscle strips, and L-732,138 at 30 and 100 μM in longitudinal muscles, though the inhibition in the latter was very weak. The results of the present study suggest that, though all mRNA coding TKs and NK-R subtypes were expressed in omasal muscle layer, NK-2R in both muscle layers and, to much lesser extent, NK-1R in longitudinal muscles are involved in the regulation of omasal contraction, and that NKA is presumably a primary non-cholinergic excitatory neurotransmitter released from motor neurons in the ovine omasum.
GR159897
2009, xPharm: The Comprehensive Pharmacology Reference
Neurobiology of generalized anxiety disorder
2001, Psychiatric Clinics of North America
Citation Excerpt :
Studies using a range of NK1 antagonists have indicated that they possess anxiolytic activity, albeit some of them weakly, but studies on NK2 receptor antagonists in animal models have invariably shown anxiolytic activity, which is robust. The most studied drugs in this group are GR-15989711 and SR-48968, which show anxiolytic activity similar to that of benzodiazepines but do not produce behavioral suppression at higher doses. Although the anxiolytic effects of NK2 receptor antagonists are compelling, these effects have been obtained only in exploration tests.
Generalized anxiety disorder (GAD) is a relatively new diagnostic entity first defined as a distinct category in the DSM-III.⁷ Two major epidemiologic studies, the National Survey of Mental Health and Well-Being² and the National Comorbidity Survey¹²⁰ have shown an incidence of 3.6% and 3.1% per year, respectively. Based on the National Comorbidity Survey data in the United States alone, more than 9 million people are afflicted with GAD at some point during their lifetimes. Also, GAD is one of the most common psychiatric disorders seen by primary care physicians.
GAD was once considered by many clinicians to be a relatively mild condition, but new scientific data have challenged the perception that GAD is mild and minimally disabling. GAD has been found to be associated with various adverse social consequences, such as being more prevalent in lower socioeconomic groups, being poorly paid, being on disability, and experiencing more marital instability and divorce than the general population.¹² GAD has a lifetime comorbidity rate of 62% with major depressive disorder (MDD), 39.5% with dysthymia, 37.6% with alcoholism, and 34.4% with social phobia. Comorbid GAD seems to be associated with an even greater level of functional impairment than GAD alone. Follow-up studies have shown a substantial impairment and even poorer outcome among people with GAD than among those with panic disorder.121, 125 Thus, it is evident that GAD is neither an infrequent nor mild condition but an important public health problem that merits additional research on treatment and mechanism of illness.
The diagnostic concept of GAD, however, is somewhat controversial. Some investigators have suggested that GAD is a residual or prodromal phase of MDD,92, 98 or a “forme fruste” of MDD.⁶¹ Other investigators have observed that it is attributable to other anxiety disorders, such as social phobia⁸¹ or panic disorder.¹¹⁴ Still others have conceptualized GAD as a dimension of personality function, a generalized anxious temperament that, when pronounced, constitutes psychopathology,⁴ whereas other investigators have conceptualized GAD as a part of a general neurotic syndrome.¹¹³ A well-designed 5-year longitudinal follow-up study, however, showed significant diagnostic stability for GAD, supporting the reliability of the diagnosis.¹²¹ Thus additional research must be carried out to clarify the diagnostic boundaries of GAD so that meaningful conclusions may be drawn from research studies.
This article provides a concise picture of preclinical and clinical research pertinent to the neurobiology of GAD. Research on functional neuroanatomy and fear circuitry; animal models relevant to GAD; research on the genetics of GAD; and neurochemistry, neurophysiology, and functional imaging studies relevant to GAD are discussed. Finally, a crucial discussion of several biological models of GAD is presented, and paths for future research are suggested.

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Regular paperGR159897, a potent non-peptide antagonist at tachykinin NK2 receptors

Abstract

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Bioorg. Med. Chem. Lett.

Life Sci.

Eur. J. Pharmacol.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Neuropeptides

Regul. Pept.

Regul. Pept.

Eur. J. Pharmacol.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Bioorg. Med. Chem. Lett.

Eur. J. Pharmacol.

Regular paper
GR159897, a potent non-peptide antagonist at tachykinin NK₂ receptors