共查询到20条相似文献,搜索用时 31 毫秒
1.
Régis Millet Jean-François Goossens Karine Bertrand-Caumont Raymond Houssin Jean-Pierre Hénichart 《Letters in Peptide Science》1999,6(4):255-262
Chemical modifications were obtained on the dual NK1/NK2 ligand Cbz-Gly-Leu-Trp-OBzl(CF3)2 with a view to optimizing affinities for both NK1 and NK2 receptors. Replacement of the Gly residue by other amino acids increased affinities for NK1/NK2 receptors or induced selectivity for the NK1 receptor. 相似文献
2.
Millet Régis Goossens Jean-François Bertrand-Caumont Karine Houssin Raymond Hénichart Jean-Pierre 《International journal of peptide research and therapeutics》1999,6(4):255-262
Summary Chemical modifications were obtained on the dual NK1/NK2 ligand Cbz-Gly-Leu-Trp-OBzl(CF3)2 with a view to optimizing affinities for both NK1 and NK2 receptors. Replacement of the Gly residue by other amino acids increased affinities for NK1/NK2 receptors or induced selectivity for the NK1 receptor. 相似文献
3.
Millet Régis Goossens Jean-François Bertrand-Caumont Karine Chavatte Philippe Houssin Raymond Hénichart Jean-Pierre 《International journal of peptide research and therapeutics》1999,6(4):221-233
Summary Chemical modifications on the NK1 competitive antagonist L-732,138, with a view to creating a dual NK1/NK2 ligand, led to the tryptophan derivative 1 possessing the protected Gly-Leu sequence of the C-terminus of substance P and
neurokinin A. Modifications in the nature of the carbamate function increased the selectivity for the NK1 receptor, whereas the inclusion of the indole moiety in β-carboline or carbazole rings decreased the affinity for both receptors.
Free indolylmethyl and Cbz carbamate groups were shown to be essential for NK2 affinity. 相似文献
4.
Régis Millet Jean-François Goossens Karine Bertrand-Caumont Philippe Chavatte Raymond Houssin Jean-Pierre Hénichart 《Letters in Peptide Science》1999,6(4):221-233
Chemical modifications on the NK1 competitive antagonist L-732,138, with a view to creating a dual NK1/NK2 ligand, led to the tryptophan derivative 1 possessing the protected Gly-Leu sequence of the C-terminus of substance P and neurokinin A. Modifications in the nature of the carbamate function increased the selectivity for the NK1 receptor, whereas the inclusion of the indole moiety in -carboline or carbazole rings decreased the affinity for both receptors. Free indolylmethyl and Cbz carbamate groups were shown to be essential for NK2 affinity. 相似文献
5.
Daniela Pinzani Anna Maria Papini Mario Chelli Mauro Ginanneschi Carlo Alberto Maggi Riccardo Patacchini Laura Quartara Gianfranco Rapi 《Letters in Peptide Science》1996,2(5):307-313
Summary The adamantane moiety was introduced in the tachykinin NK2 receptor-selective agonist [-Ala8]-NKA(4–10) (H-Asp-Ser-Phe-Val--Ala-Leu-Met-NH2, MEN 10210) and in different positions of the NK2 receptor antagonist MEN 10376 (H-Asp-Tyr-d-Trp-Val-d-Trp-d-Trp-Lys-NH2) in order to investigate how this substitution affects their biological activity at tachykinin NK1, NK2 and NK3 receptors. 1-Adamantaneacetic acid (1-Ada-CH2COOH) was directly conjugated in the solid phase as the preformed OBt active ester to the N-terminal position of MEN 10210, obtaining MEN 10586 (1-Ada-CH2CO-Asp-Ser-Phe-Val--Ala-Leu-Met-NH2). The Pfp ester of adamantaneacetic acid (1) was prepared and used for the acylation of the N-terminal position of MEN 10376, yielding MEN 10606 (1-Ada-CH2CO-Asp-Tyr-d-Trp-Val-d-Trp-d-Trp-Lys-NH2). Compound 1 was then used to obtain the building block Fmoc-Lys(1-Ada-CH2CO)-OH as a modified amino acid for the synthesis of MEN 10818 [H-Asp-Tyr-d-Trp-Val-d-Trp-d-Trp-Lys(1-Ada-CH2CO)-NH2]. In order to investigate the biological activity of the peptide bearing the adamantane group together with the free N-terminal amino function, we synthesised MEN 10676 [H-Asp(O-2-Ada)-Tyr-d-Trp-Val-d-Trp-d-Trp-Lys-NH2] using Fmoc-Asp(O-2-Ada)-OH, in which 2-adamantanole was the protecting group of the aspartate -COOH moiety during the peptide synthesis and survived the final peptide cleavage and deprotection carried out under controlled conditions. MEN 10586 showed an agonist activity comparable to that of the parent compound MEN 10210 at NK1 and NK2 receptors of guinea pig ileum, rabbit isolated pulmonary artery and hamster isolated trachea preparations, while it showed a 25-fold higher agonist activity at NK3 receptors of rat isolated portal vein. The three modified antagonist analogs displayed similar or reduced affinity at NK1, NK2 and NK3 receptors as compared to MEN 10376. The drop was particularly evident (>2 log units) at the NK2 receptors of the rabbit isolated pulmonay artery. 相似文献
6.
Kevin W. Gillman Michael F. Parker Mark Silva Andrew P. Degnan George O. Tora Nicholas J. Lodge Yu-Wen Li Snjezana Lelas Matthew Taber Rudolf G. Krause Robert L. Bertekap Amy E. Newton Rick L. Pieschl Kelly D. Lengyel Kim A. Johnson Sarah J. Taylor Joanne J. Bronson John E. Macor 《Bioorganic & medicinal chemistry letters》2013,23(2):407-411
A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK1/SERT affinity. Optimization based on NK1/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK1/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression. 相似文献
7.
Juhl K Hansen T Kehler J Khanzhin NA Nørgaard MB Ruhland T Larsen DB Jensen KG Steiniger-Brach B Nielsen SM Simonsen KB 《Bioorganic & medicinal chemistry letters》2011,21(5):1498-1501
The identification and structure-activity relationships of 2-aminomethyl-1-aryl cyclopropane carboxamides as novel NK3 receptor antagonists are reported. The compound series was optimized to give analogues with low nanomolar binding to the NK3 receptor and brain exposure, leading to activity in vivo in the senktide-induced hypoactivity model in gerbils. 相似文献
8.
Juan-Carlos Pelayo Nicholas A. Veldhuis Emily M. Eriksson Nigel W. Bunnett Daniel P. Poole 《Cell and tissue research》2014,356(2):319-332
The substance P neurokinin 1 receptor (NK1R) regulates motility, secretion, inflammation and pain in the intestine. The distribution of the NK1R is a key determinant of the functional effects of substance P in the gut. Information regarding the distribution of NK1R in subtypes of mouse enteric neurons is lacking and is the focus of the present study. NK1R immunoreactivity (NK1R-IR) is examined in whole-mount preparations of the mouse distal colon by indirect immunofluorescence and confocal microscopy. The distribution of NK1R-IR within key functional neuronal subclasses was determined by using established neurochemical markers. NK1R-IR was expressed by a subpopulation of myenteric and submucosal neurons; it was mainly detected in large multipolar myenteric neurons and was colocalized with calcitonin gene-related peptide, neurofilament M, choline acetyltransferase and calretinin. The remaining NK1R-immunoreactive neurons were positive for nitric oxide synthase. NK1R was expressed by most of the submucosal neurons and was exclusively co-expressed with vasoactive intestinal peptide, with no overlap with choline acetyltransferase. Treatment with substance P resulted in the concentration-dependent internalisation of NK1R from the cell surface into endosome-like structures. Myenteric NK1R was mainly expressed by intrinsic primary afferent neurons, with minor expression by descending interneurons and inhibitory motor neurons. Submucosal NK1R was restricted to non-cholinergic secretomotor neurons. These findings highlight key differences in the neuronal distribution of NK1R-IR between the mouse, rat and guinea-pig, with important implications for the functional role of NK1R in regulating intestinal motility and secretion. 相似文献
9.
《Bioorganic & medicinal chemistry letters》2014,24(2):510-514
The tachykinin NK1 and NK3 receptors are a novel drug target for schizophrenia in order to treat not only the positive and cognitive symptoms, but also the associated co-morbid depression and sleep disturbances associated with the disease. A novel class of peptidomimetic derivatives based on a versatile phenylglycine central core was synthesized and tested in vitro as dual NK1/NK3 receptor antagonists. From this series emerged compounds with good NK1 receptor affinity, although only modest dual NK1/NK3 receptor affinity was observed with one of these analogs. 相似文献
10.
Romano Di Fabio Giuseppe Alvaro Simone Braggio Renzo Carletti Philip A. Gerrard Cristiana Griffante Carla Marchioro Alfonso Pozzan Sergio Melotto Alessandro Poffe Laura Piccoli Emiliangelo Ratti Elvira Tranquillini Michael Trower Simone Spada Mauro Corsi 《Bioorganic & medicinal chemistry》2013,21(21):6264-6273
The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 receptor (NK1) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK1 receptor antagonist aprepitant has been approved as a therapeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK1 receptor antagonists had yet to be realized; therefore clinical evidence that NK1 receptor antagonists may be effective in major depression disorder, resulted in a significant further investment in discovering novel CNS penetrant druggable NK1 receptor antagonists to address this condition. At GlaxoSmithKline after the discovery of casopitant, that went on to demonstrate efficacy as a novel antidepressant in the clinic, additional novel analogues of this NK1 receptor antagonist were designed to further enhance its drug developability characteristics. Herein, we therefore describe the discovery process and the vivo pharmacological and pharmacokinetic profile of the new NK1 receptor antagonist 3a (also called orvepitant), selected as clinical candidate and further progressed into clinical studies for major depressive disorder. Moreover, molecular modeling studies enabled us to improve the pharmacophore model of the NK1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties. 相似文献
11.
Shigetomo Fukuhara Hidehito Mukai Koichiro Kako Kazuhisa Nakayama Eisuke Munekata 《Journal of neurochemistry》1996,67(3):1282-1292
Abstract: It has been suggested that murine neuroblastoma C1300 cells express endogenous neurokinin NK2 receptors with features that differ from those of NK2 receptors characterized in other systems. In this study, we have further characterized the neurokinin receptor types present in this cell line. RNA blots showed that mRNAs of NK2 and NK3 receptors, but not of NK1 receptors, were expressed in C1300 cells. The increase in the cytosolic calcium concentration ([Ca2+]i) induced by 0.33 µM neurokinin A was completely inhibited by SR 48968, an NK2 receptor antagonist, whereas the partial response to 0.33 µM neurokinin B was unaffected, and the response was completely inhibited by SR 142801, an NK3 receptor antagonist. In addition, the [Ca2+]i increase by 0.33 µM senktide, an NK3 receptor agonist, was inhibited by SR 142801 but not by SR 48968. These findings indicated that C1300 cells endogenously express functional NK2 and NK3 receptors. It was also demonstrated that NK2 and NK3 receptors can be activated independently by 3.3 µM neurokinin A in the presence of 1.0 µM SR 142801 or 1.0 µM senktide, respectively. Therefore, the mechanisms of Ca2+ signaling mediated by endogenous NK2 and NK3 receptors were investigated. The independent activation of NK2 or NK3 receptors induced not only the [Ca2+]i increase, but also stimulated the formation of inositol trisphosphates; both these responses were inhibited by U73122, a phospholipase C (PLC) inhibitor. In addition, NK2 and NK3 receptor-mediated [Ca2+]i increase was partially attenuated in the absence of extracellular Ca2+ or in the presence of nickel, an inorganic Ca2+ influx blocker, but was unaffected by nifedipine and ω-conotoxin, L- and N-type voltage-dependent Ca2+ channel blockers, respectively. Furthermore, the depolarization by 60 mM K+ did not affect the [Ca2+]i. These findings suggested that the NK2 and NK3 receptor-mediated [Ca2+]i increase was due to the activation of PLC and was dependent on the mobilization of internal Ca2+ and the entry of extracellular Ca2+ through voltage-independent channels. This study showed that the C1300 cell line is a useful system with which to investigate pharmacological functions and signaling pathways of endogenous NK2 and NK3 receptors. 相似文献
12.
K. M. Jenkinson Jan M. Morgan John B. Furness Bridget R. Southwell 《Histochemistry and cell biology》1999,112(3):233-246
The localisation of NK3 tachykinin receptors in guinea-pig ileum was studied using the fluorescently labelled agonists, Cy3.5-neurokinin A and Cy3.5-kassinin.
Binding to nerve cell bodies in the myenteric and submucosal plexuses was visualised using confocal microscopy. Binding to
NK1 receptors was blocked by the NK1 receptor antagonist, CP-99994. NK3 receptors, demonstrated by binding in the presence of CP-99994, occurred in 72% of myenteric and 38% of submucosal neurons.
Colocalisation with other markers was examined to deduce the classes of neurons with NK3 receptors. In myenteric ganglia, NK3 receptors were present on the following: 73% of calbindin-immunoreactive (IR) intrinsic primary afferent neurons, 63% of
calretinin-IR excitatory motor neurons and ascending interneurons, 63% of nitric oxide synthase-IR inhibitory motor neurons
and descending interneurons, 79% of strongly neuropeptide Y (NPY)-IR secretomotor neurons, 67% of weakly NPY-IR descending
interneurons and motor neurons, and 46% of NK1 receptor-IR neurons. In submucosal ganglia, NK3 receptors were on 65% of calretinin-IR secretomotor/vasodilator neurons, 81% of NPY-IR cholinergic secretomotor neurons,
2% of vasoactive intestinal peptide-IR non-cholinergic secretomotor neurons and were completely absent from substance P-IR
intrinsic primary afferent neurons. The results support physiological studies suggesting that NK3 receptors mediate tachykinin transmission between myenteric sensory neurons and to interneurons and/or motor neurons in descending
inhibitory and ascending excitatory pathways.
Accepted: 22 June 1999 相似文献
13.
The tachykinins, substance P (SP) and neurokinin A (NKA), are agonists for the NK1 and NK2 receptors, respectively. Tachykinins have various respiratory effects, including bronchoconstriction. This study characterizes
tachykinin binding sites in the rabbit lung. We hypothesize that (2-[125I]iodohistidyl1)Neurokinin A ([125I]NKA) interacts with NK1 and NK2 binding sites in the rabbit lung. The Kd determined from saturation isotherms was 0.69 X/÷1.14 nM (geometic mean X/÷ SEM) and the Bmax was 4.15±0.22 femtomole/mg protein (arithmetic mean±SEM). Competitive inhibition studies with NKA, SP and various selective
tachykinin agonists showed the rank order of potency: [β-Ala8]-Neurokinin A 4–10=SP ≫ NKA ≫ [Sar9,Met(O2)11]-Substance P. [β-Ala8]-Neurokinin A 4–10, a selective NK2 agonist, and SP inhibition of [125I]NKA binding were best described using a two-site model. Competitive inhibition studies using the selective nonpeptide NK2 antagonist (SR 48968) and the selective nonpeptide NK1 antagonist (CP 96,345) revealed Ki's of 5.5 nM and 8.1 nM, respectively. Our data therefore suggest that [125I]NKA binds to both the NK1 and NK2 receptors in the lung.
Special issue dedicated to Dr. Kinya Kuriyama. 相似文献
14.
Scarrone S Cappelli A Cupello A Matarrese M Moresco RM Fazio F 《Neurochemical research》2003,28(8):1159-1162
The binding of 125I-labeled substance P (SP) to rat brain cortex membranes has been studied Under control conditions and in the presence of ethanol. The binding of SP at low concentrations (20–1000 pM) gave two components, one with a K
D value of 80 pM and another one with a K
D of 500 pM. The higher-affinity component is due to NK1 receptors, as confirmed by the inhibition Of the SP binding by the rodent NK1 specific agonist [Sar9 Met(O2)11]SP. Ethanol (1.7 mM) added to the binding assays inhibited by more than 50% the specific binding at a very low SP concentration (20 pM); however, it had no effect at SP concentrations ranging from 50 to 120 pM. This suggests a decrease by ethanol of the affinity of SP to the NK1 receptors involved in this binding component. The ethanol effect disappeared at [EtOH] 0.17 mM. 相似文献
15.
Solo Goldstein Michel Neuwels Florence Moureau Didier Berckmans Marie-Agnès Lassoie Edmond Differding Raymond Houssin Jean-Pierre Hénichart 《Letters in Peptide Science》1995,2(3-4):125-134
Summary Nine potent and selective substance P receptor antagonists (NK1
-) were analyzed with respect to their conformational space, with the aim to suggest probable conformations adopted at the receptor site and superposition rules for each structure (pharmacophore mapping). Key atoms within the ligands as well as receptor site points were considered in order to identify acceptable solutions (DISCO program). The results obtained allowed the suggestion or probable peptidic pharmacophores based on the structure of 1 (FK888). This knowledge was used to search commercial databases. The number and diversity of known retrieved NK1 antagonists allowed a general evaluation of the proposed pharmacophores. Moreover, a search in our proprietary database detected a short peptide with modest affinity but high selectivity for the NK1 receptor. The combination of molecular modeling with database searches is useful in a strategy aiming to develop new NK1 antagonists starting from existing knowledge. 相似文献
16.
Yong-Jin Wu Huan He Robert Bertekap Ryan Westphal Snjezana Lelas Amy Newton Tanya Wallace Matthew Taber Carl Davis John E. Macor Joanne Bronson 《Bioorganic & medicinal chemistry》2013,21(8):2217-2228
This report describes the synthesis, structure–activity relationships and activity of piperidine, homopiperidine, and azocane derivatives combining NK1 receptor (NK1R) antagonism and serotonin reuptake transporter (SERT) inhibition. Our studies culminated in the discovery of piperidine 2 and homopiperidine 8 as potent dual NK1R antagonists-SERT inhibitors. Compound 2 demonstrated significant activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders. 相似文献
17.
Marina Candido Primi Vinícius Gonçalves Maltarollo Juliana Gallottini Magalhães Matheus Malta de Sá Carlota Oliveira Rangel-Yagui 《Journal of enzyme inhibition and medicinal chemistry》2016,31(2):283-294
The dopamine hypothesis states that decreased dopaminergic neurotransmission reduces schizophrenia symptoms. Neurokinin-3 receptor (NK3) antagonists reduce dopamine release and have shown positive effects in pre-clinical and clinical trials. We employed 2D and 3D-QSAR analysis on a series of 40 non-peptide NK3 antagonists. Multivariate statistical analysis, PCA and HCA, were performed to rational training/test set splitting and PLS regression was employed to construct all QSAR models. We constructed one highly predictive CoMFA model (q2?=?0.810 and r2?=?0.929) and acceptable HQSAR and CoMSIA models (HQSAR q2?=?0.644 and r2?=?0.910; CoMSIA q2?=?0.691, r2?=?0.911). The three different techniques provided convergent physicochemical results. All models indicate cyclopropane, piperidine and di-chloro-phenyl ring attached to cyclopropane ring and also the amide group attached to the piperidine ring could play an important role in ligand–receptor interactions. These findings may contribute to develop potential NK3 receptor antagonists for schizophrenia. 相似文献
18.
Katelijne O De Swert Ken R Bracke Tine Demoor Guy G Brusselle Guy F Joos 《Respiratory research》2009,10(1):37
Background
The tachykinins, substance P and neurokinin A, present in sensory nerves and inflammatory cells such as macrophages and dendritic cells, are considered as pro-inflammatory agents. Inflammation of the airways and lung parenchyma plays a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and increased tachykinin levels are recovered from the airways of COPD patients. The aim of our study was to clarify the involvement of the tachykinin NK1 receptor, the preferential receptor for substance P, in cigarette smoke (CS)-induced pulmonary inflammation and emphysema in a mouse model of COPD.Methods
Tachykinin NK1 receptor knockout (NK1-R-/-) mice and their wild type controls (all in a mixed 129/sv-C57BL/6 background) were subjected to sub acute (4 weeks) or chronic (24 weeks) exposure to air or CS. 24 hours after the last exposure, pulmonary inflammation and development of emphysema were evaluated.Results
Sub acute and chronic exposure to CS resulted in a substantial accumulation of inflammatory cells in the airways of both WT and NK1-R-/- mice. However, the CS-induced increase in macrophages and dendritic cells was significantly impaired in NK1-R-/- mice, compared to WT controls, and correlated with an attenuated release of MIP-3α/CCL20 and TGF-β1. Chronic exposure to CS resulted in development of pulmonary emphysema in WT mice. NK1-R-/- mice showed already enlarged airspaces upon air-exposure. Upon CS-exposure, the NK1-R-/- mice did not develop additional destruction of the lung parenchyma. Moreover, an impaired production of MMP-12 by alveolar macrophages upon CS-exposure was observed in these KO mice. In a pharmacological validation experiment using the NK1 receptor antagonist RP 67580, we confirmed the protective effect of absence of the NK1 receptor on CS-induced pulmonary inflammation.Conclusion
These data suggest that the tachykinin NK1 receptor is involved in the accumulation of macrophages and dendritic cells in the airways upon CS-exposure and in the development of smoking-induced emphysema. As both inflammation of the airways and parenchymal destruction are important characteristics of COPD, these findings may have implications in the future treatment of this devastating disease. 相似文献19.
Dong Xiao Cheng Wang Anandan Palani Hon-Chung Tsui Gregory Reichard Sunil Paliwal Neng-Yang Shih Robert Aslanian Ruth Duffy Jean Lachowicz Geoffrey Varty Cynthia Morgan Fei Liu Amin Nomeir 《Bioorganic & medicinal chemistry letters》2010,20(21):6313-6315
Modification of prototype NK1 antagonist 2 resulted in the synthesis of a series of simple amides 6 and retroamides 9. These compounds were shown to be potent and orally active NK1 antagonists. 相似文献
20.
Yvette Torrens Jean-Claude Beaujouan Monique Saffroy Jacques Glowinski Martine Tencé 《Journal of neurochemistry》1998,70(5):2091-2098
Abstract: In [3H]myristic acid-prelabeled Chinese hamster ovary cells stably expressing the rat NK1 tachykinin receptor, the selective NK1 agonist [Pro9]substance P ([Pro9]SP) time and concentration dependently stimulated the formation of [3H]phosphatidylethanol in the presence of ethanol. This [Pro9]SP-induced activation of phospholipase D (PLD) was blocked by NK1 receptor antagonists and poorly or not mimicked by NK2 and NK3 agonists, respectively. In confirmation of previous observations, [Pro9]SP also stimulated the hydrolysis of phosphoinositides, the release of arachidonic acid, and the formation of cyclic AMP (cAMP). All these [Pro9]SP-evoked responses could be mimicked by aluminum fluoride, but they remained unaffected in cells pretreated with pertussis toxin, suggesting that a Gi/Go protein is not involved in these different signaling pathways. The activation of PLD by [Pro9]SP was sensitive to external calcium and required an active protein kinase C because the inhibition of this kinase (Ro 31-8220) or its down-regulation (long-term treatment with a phorbol ester) abolished the response. In contrast, a cAMP-dependent process was not involved in the activation of PLD because the [Pro9]SP-evoked response was neither affected by Rp-8-bromoadenosine 3′,5′-cyclic monophosphorothioate nor mimicked by cAMP-generating compounds (cholera toxin or forskolin) or by 8-bromo-cyclic AMP. A functional coupling of NK1 receptors to PLD was also demonstrated in the human astrocytoma cell line U 373 MG stimulated by SP or [Pro9]SP. These results suggest that PLD activation could be an additional signaling pathway involved in the mechanism of action of SP in target cells expressing NK1 receptors. 相似文献