Neurokinin

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James E. Krause - One of the best experts on this subject based on the ideXlab platform.

  • Similar rates of phosphatidylinositol hydrolysis following activation of wild-type and truncated rat Neurokinin-1 receptors
    Journal of neurochemistry, 2002
    Co-Authors: Rita Raddatz, Carolyn L. Crankshaw, R. Michael Snider, James E. Krause
    Abstract:

    The substance P (Neurokinin-1) receptor belongs to the family of seven putative transmembrane domain receptors that are coupled via G proteins to phospholipase C activation. Homologous desensitization of substance P-stimulated responses has been described in various systems. The rat Neurokinin-1 receptor and a truncated mutant lacking the carboxyl-terminal region were expressed in Chinese hamster ovary cells to examine the mechanisms of substance P-induced desensitization. Wild-type and truncated receptor-bearing cells were indistinguishable in agonist binding affinity and EC 50 of substance P-induced accumulation of 3 H-inositol phosphates. Substance P-induced responses continued for 30-45 min in cells expressing wild-type and truncated receptors as well as in rat LRM-55 and human U373 cells, which express endogenous Neurokinin-1 receptors. In transfected cells expressing the wild-type receptor, CP-96,345 added 15 min after substance P blocked further responses, demonstrating the continuing presence of responsive receptors. The rates of accumulation of 3 H-inositol phosphates were four times greater in the initial 15 s of stimulation than for the next 20 min for both wildtype and truncated receptor types. This decrease in rate of substance P-stimulated phosphatidylinositol hydrolysis is therefore not dependent on the carboxyl-terminal region of the rat Neurokinin-1 receptor, which contains 26 serine and threonine residues. These results are discussed in relation to current ideas regarding Neurokinin-1 receptor desensitization

  • functional expression of a novel human Neurokinin 3 receptor homolog that binds 3h senktide and 125i mephe7 Neurokinin b and is responsive to tachykinin peptide agonists
    Proceedings of the National Academy of Sciences of the United States of America, 1997
    Co-Authors: James E. Krause, P T Staveteig, Nave J Mentzer, S K Schmidt, J B Tucker, R M Brodbeck, V V Karpitskiy
    Abstract:

    In 1992, Xie et al. identified a cDNA sequence in the expression cloning search for the κ opioid receptor. When the cDNA was expressed in Cos-7 cells, binding of opioid compounds was observed to be of low affinity and without κ, μ, or δ selectivity [Xie, G.-X., Miyajima, A. and Goldstein, A. (1992) Proc. Natl. Acad. Sci. USA 89, 4124–4128]. This cDNA was highly homologous to the human Neurokinin-3 (NK-3) receptor sequence, and displayed lower homology to NK-1 and NK-2 sequences. This sequence was stably expressed in Chinese hamster ovary cells, which do not express Neurokinin receptors naturally, and ligand binding and second messenger characteristics were compared with a human NK-3 receptor. The NK-3 receptor homolog bound [3H]senktide with a Kd of 39 nM, similar to that of the NK-3 receptor. The rank order of tachykinin peptides competing for [3H]senktide binding at the NK-3 receptor homolog was [MePhe7]Neurokinin B > senktide > substance P = Neurokinin A > Neurokinin B. This cell line also bound [125I-MePhe7]Neurokinin B; however, Neurokinin B was an effective competitor. Tachykinin peptides stimulated both inositol phospholipid hydrolysis and arachidonic acid release at NK-3 and NK-3 receptor homolog cell lines, with similar rank orders of potency of [MePhe7]Neurokinin B = Neurokinin B = senktide > NKA = substance P. These results indicate that expression of the NK-3 receptor homolog cDNA in the Chinese hamster ovary cell system induces the expression of a receptor site with many similarities but certain key differences from that of the human NK-3 receptor. The results are discussed with reference to the existence of a novel human tachykinin receptor.

  • The formalin-induced expression of tachykinin peptide and Neurokinin receptor messenger RNAs in rat sensory ganglia and spinal cord is modulated by opiate preadministration.
    Neuroscience, 1995
    Co-Authors: Kenneth E. Mccarson, James E. Krause
    Abstract:

    Abstract Tachykinin peptides such as substance P and Neurokinin B have been widely studied as mediators of pain transmission. The expression of Neurokinin-1 and Neurokinin-3 receptor messenger RNAs in the spinal cord is increased following intense nociception. The opiate ligands morphine and naltrexone alter behavioral responses to formalin-induced pain and alter evoked substance P release. This study investigated whether these opiates similarly alter the expression of substance P-, Neurokinin B-, Neurokinin-1 receptor- and Neurokinin-3 receptor-encoding messenger RNAs in spinal systems following formalin-induced nociception. Expression levels of various messenger RNAs were quantitated using solution hybridization-nuclease protection assays. Six hours after hindpaw treatment, the levels of substance P-encoding preprotachykinin messenger RNA in the lumbar dorsal root ganglia and Neurokinin B, Neurokinin-1 receptor and Neurokinin-3 receptor messenger RNAs in the lumbar dorsal horn were increased by approximately two-fold as compared to sham-treated controls. Pretreatment with naltrexone resulted in a further increase in the nociception-induced substance P messenger RNA expression in the dorsal root ganglia; preprotachykinin messenger RNA expression was not affected by morphine. Nociception-induced Neurokinin-1 receptor messenger RNA expression in the dorsal horn was blocked by morphine, but was not affected by naltrexone. Both morphine and naltrexone blocked the formalin-induced increases in Neurokinin B and Neurokinin-3 receptor messenger RNA levels. Increased Neurokinin B messenger RNA expression may reflect increased Neurokinin B turnover in spinal interneurons activated by nociception. Neurokinin-3 receptor messenger RNA expression levels varied closely with, and thus may be regulated by, the levels of Neurokinin B messenger RNA in the same regions. The results of this study indicate that pretreatment with opiate ligands modulates the expression of tachykinin peptide and Neurokinin receptor encoding mRNAs in spinal systems following a peripheral chemogenic inflammatory stimulus. Thus, endogenous opioid systems may be involved in activity-induced changes in the expression of spinal tachykinin peptides and Neurokinin receptors.

James J. Foley - One of the best experts on this subject based on the ideXlab platform.

  • Nonpeptide tachykinin receptor antagonists. III. SB 235375, a low central nervous system-penetrant, potent and selective Neurokinin-3 receptor antagonist, inhibits citric acid-induced cough and airways hyper-reactivity in guinea pigs.
    Journal of Pharmacology and Experimental Therapeutics, 2002
    Co-Authors: Douglas W. P. Hay, Giuseppe Giardina, William Potts, Don E. Griswold, David C. Underwood, Charles J. Kotzer, Brian Bush, Punam Sandhu, Dave Lundberg, James J. Foley
    Abstract:

    In this report the in vitro and in vivo pharmacological and pharmacokinetic profile of (−)-( S )- N -(α-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide (SB 235375), a low central nervous system (CNS)-penetrant, human Neurokinin-3 (NK-3) receptor (hNK-3R) antagonist, is described. SB 235375 inhibited 125I-[MePhe7]-Neurokinin B (NKB) binding to membranes of Chinese hamster ovary (CHO) cells expressing the hNK-3R (CHO-hNK-3R) with a K i = 2.2 nM and antagonized competitively NKB-induced Ca2+ mobilization in human embryonic kidney (HEK) 293 cells expressing the hNK-3R (HEK 293-hNK-3R) with a K b = 12 nM. SB 235375 antagonized senktide (NK-3R)-induced contractions in rabbit isolated iris sphincter (pA2 = 8.1) and guinea pig ileal circular smooth muscles (pA2 = 8.3). SB 235375 was selective for the hNK-3R compared with hNK-1 ( K i > 100,000 nM) and hNK-2 receptors ( K i = 209 nM), and was without effect, at 1 μM, in 68 other receptor, enzyme, and ion channel assays. Intravenous SB 235375 produced a dose-related inhibition of miosis induced by i.v. senktide in the rabbit (ED50 of 0.56 mg/kg). Intraperitoneal SB 235375 (10–30 mg/kg) inhibited citric acid-induced cough and airways hyper-reactivity in guinea pigs. In mice oral SB 235375 (3–30 mg/kg) was without significant effect on the behavioral responses induced by intracerebral ventricular administration of senktide. Pharmacokinetic evaluation in the mouse and rat revealed that oral SB 235375 was well absorbed systemically but did not effectively cross the blood-brain barrier. The preclinical profile of SB 235375, encompassing high affinity, selectivity, oral activity, and low CNS penetration, suggests that it is an appropriate tool compound to define the pathophysiological roles of the NK-3Rs in the peripheral nervous system. * NKA : Neurokinin A NKB : Neurokinin B CNS : central nervous system NK-1R : Neurokinin-1 receptor NK-2R : Neurokinin-2 receptor NK-3 : Neurokinin-3 NK-3R : Neurokinin-3 receptor PEG : polyethylene glycol CHO : Chinese hamster ovary CHO-hNK-3R : CHO cells stably expressing the human NK-3R CHO-hNK-2R : CHO cells stably expressing the human NK-2R CHO-hNK-1R : CHO cells expressing the human NK-1R HEK : human embryonic kidney HEK 293-hNK-3R : HEK 293 cells stably expressing the human NK-3R HEK 293-mNK-3R : HEK 293 cells transiently expressing the murine NK-3R HEK 293-mNK-2R : HEK 293 cells transiently expressing the murine NK-2R IC50 : concentration of antagonist causing 50% inhibition of agonist response K i : apparent inhibition constant K b : dissociation constant ANOVA : analysis of variance 5-HT : serotonin (5-hydroxytryptamine)

  • 2 phenyl 4 quinolinecarboxamides a novel class of potent and selective non peptide competitive antagonists for the human Neurokinin 3 receptor
    Journal of Medicinal Chemistry, 1996
    Co-Authors: Giuseppe Giardina, James J. Foley, Henry M Sarau, Carlo Farina, Andrew D Medhurst, Mario Grugni, Luca Francesco Raveglia, Dulcie B Schmidt, Roberto Rigolio, Marco Vassallo
    Abstract:

    Pharmacological and molecular biological studies indicate the existence of at least three human tachykinin receptor subtypes, designated Neurokinin-1 (NK-1), Neurokinin-2 (NK-2), and Neurokinin-3 (NK-3),1-3 which belong to the superfamily of G-protein-coupled receptors possessing seven transmembrane domains.4 The endogenous ligands for these receptors constitute a family of small neuropeptides, named tachykinins or Neurokinins, which share the common carboxy-terminal region Phe-X-Gly-Leu-MetNH2. The main mammalian tachykinins, substance P, Neurokinin A (NKA), and Neurokinin B (NKB), interact with all three tachykinin receptors, although there is a defined agonist rank order of potency for NK-1, NK-2, and NK-3 receptors, respectively; for example, for the NK-3 receptor the rank potency order is NKB > NKA > substance P. Over the past few years potent and selective peptide and non-peptide antagonists for the NK-1 and NK-2 receptors have been identified.5-8 These pharmacological tools accelerated the clarification of physiological and pathophysiological roles of these receptors9 and the potential therapeutic indications for NK-1 and NK-2 receptor antagonists.10-13 In contrast to the NK-1 and NK-2 receptor research area, there is limited information on the biology and potential pathophysiological significance of the NK-3 receptor. This was, to a large extent, due to the lack of sufficient potency and selectivity of the peptide NK-3 antagonists described thus far14 and to the absence of non-peptide NK-3 receptor ligands until recently. However, the recent disclosure of the “peptoid” NK-3 antagonist PD 15767215 and the peptidederived PD 16118216 has provided improved reagents for these studies and stimulated the search for more potent and metabolically stable non-peptide NK-3 receptor antagonists. The human NK-3 (hNK-3) receptor mRNA has been detected, using polymerase chain reaction (PCR), to various regions in the central nervous system (CNS) and also, albeit to a lesser extent, in some peripheral tissues, including kidney, placenta, lung, and colon.17 Activation of NK-3 receptors modulates the release of various transmitters in the CNS and periphery,18-20 suggesting that they may have a neuromodulatory role. Recently, (S)-(+)-N-{{3-[1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]prop-1-yl}-4-phenylpiperidin-4-yl}-Nmethylacetamide, SR 142801 (1, Chart 1), was reported as the first potent non-peptide NK-3 receptor antagonist.21,22 Chemically, SR 142801 derives from a constrained analog of SR 48968, a potent NK-2 receptor antagonist (Ki ) 0.51 nM, for displacement of [125I]NKA) in rat duodenum membranes,7 which has moderate affinity for NK-3 receptors (IC50 ) 320 nM, for displacement of [3H]senktide {succinyl-[Asp9MePhe8]SP(6-13)}) in guinea pig cerebral cortex membranes.23 We now report on the discovery of a novel class of potent and selective non-peptide NK-3 receptor antagonistssstructurally unrelated to the piperidine derivatives SR 142801 and SR 48968swhich are based on the 2-phenylquinoline backbone.24 Chemical synthesis (Scheme 1), radioligand binding affinities for the cloned human Neurokinin receptors stably expressed in CHO cell lines (hNKs-CHO),17,25,26 in vitro functional activity in the rabbit isolated iris sphincter muscle preparation (antagonism of senktide-induced contraction),27 and structure-activity relationships (SARs) of the novel † Italy. ‡ USA. § England. © Copyright 1996 by the American Chemical Society

B Kerdelhue - One of the best experts on this subject based on the ideXlab platform.

  • substance p and Neurokinin a variations throughout the rat estrous cycle comparison with ovariectomized and male rats ii trigeminal nucleus and cervical spinal cord
    Journal of Neuroscience Research, 1996
    Co-Authors: Pierre Duval, Saliha Moussaoui, V Lenoir, Claude Garret, B Kerdelhue
    Abstract:

    Substance P and Neurokinin A were assayed in the trigeminal nucleus and cervical spinal cord of 4-day cycling female, ovariectomized, and male rats. During the estrous cycle, levels were largely stable in the trigeminal nucleus. In ovariectomized rats, the levels differed from those on any day of the estrous cycle suggesting a weak effect of ovarian steroids. In males, the variations in the substance P and Neurokinin A contents in the trigeminal nucleus were not similar to those in either cyclic or ovariectomized rats. The levels fluctuated substantially in the cervical spinal cord. During the first 3 days of the estrous cycle, the substance P and Neurokinin A contents fell concomitant with the 17 beta-estradiol surge, suggesting a downregulation of substance P and Neurokinin A contents by 17 beta-estradiol. Furthermore, on estrus, progesterone seemed to inhibit the accumulation of both Neurokinins. Testosterone may stimulate accumulation of substance P and Neurokinin A in the cervical spinal cord, with a marked circadian rhythm. These results are in favor of the Neurokinin content of the spinal cord being regulated by the gonadal steroids. In the trigeminal nucleus, only testosterone has an effect.

  • substance p and Neurokinin a variations throughout the rat estrous cycle comparison with ovariectomized and male rats i plasma hypothalamus anterior and posterior pituitary
    Journal of Neuroscience Research, 1996
    Co-Authors: Pierre Duval, Saliha Moussaoui, V Lenoir, Claude Garret, B Kerdelhue
    Abstract:

    The concentrations of Substance P and Neurokinin A were measured in plasma, and the hypothalamo-pituitary complex of 4-day-cycling female, ovariectomized and male rats. Estrous cycle-related fluctuations were recorded for these two Neurokinins. The patterns of plasma concentrations of Substance P and Neurokinin A, however, were not similar throughout the rat estrous cycle. The plasma concentration of Substance P increased on proestrus at 19.00 hr, while Neurokinin A decreased. The plasma concentration of Substance P was positively correlated with plasma 17 beta-estradiol levels. In the ovariectomized rat, the absence of ovarian steroids led to low levels of plasma Neurokinin A, but the plasma concentration of Substance P did not show any change as compared to the estrous cycle. In the male rat, a similar observation was made in the presence of a testosterone environment. The largest variations in tissue concentration of both peptides were observed in the anterior pituitary. Substance P and Neurokinin A contents were higher throughout the proestrous day than the 3 other days. However, the level fell at 18.00 hr on proestrus, and there were similar falls in the hypothalamic contents of Substance P and Neurokinin A at 19.00 hr. In the ovariectomized rat, with no gonadal steroids, the hypothalamic and/or anterior pituitary levels of Substance P were in the same range as during the estrous cycle. However, the hypothalamic levels of Neurokinin A were lower and Neurokinin A was undetectable in the anterior pituitary. Substance P and Neurokinin A concentrations in the posterior pituitary were stable throughout the estrous cycle, with the exception of rises for both peptides on estrous day. Substance P levels were much lower in ovariectomized and male rats. These results describe large fluctuations in hypothalamic and pituitary Substance P and Neurokinin A contents through the estrous cycle in the female rat. They also strongly suggest the involvement of gonadal steroids in the differential regulation of Substance P and Neurokinin A in the female and male rat.

Christopher E. Jones - One of the best experts on this subject based on the ideXlab platform.

  • Endocytic recycling prevents copper accumulation in astrocytoma cells stimulated with copper-bound Neurokinin B.
    Biochemical and Biophysical Research Communications, 2020
    Co-Authors: Resmi Menon, Katerina Christofides, Christopher E. Jones
    Abstract:

    Abstract Neurokinin B (NKB) is a key neuropeptide in reproductive endocrinology where it contributes to the generation of pulses of gonadotropin-releasing hormone. NKB is a copper-binding peptide; in the absence of metal NKB rapidly adopts an amyloid structure, but copper binding inhibits amyloid formation and generates a structure that can activate the Neurokinin 3 receptor. The fate of copper once it binds NKB and activates the Neurokinin 3 receptor is not understood, but endocytosis of NKB occurs even when the peptide is coordinated to copper. Using astrocytoma cells that express endogenous Neurokinin 3 receptor, this work shows that endocytosis of apo- and copper-bound NKB occurs in concert with the receptor via a trafficking pathway that includes the early endosome. When cells are stimulated with copper-bound NKB the cellular copper concentration does not significantly increase, however when the cells are pre-treated with the recycling inhibitor, brefeldin A, they are capable of accumulating copper. This data shows that copper-bound NKB can activate the Neurokinin 3 receptor then endocytosis abstracts metal, peptide and receptor from the cell surface. The cell does not accumulate the copper but instead it enters recycling pathways that ultimately leads to metal release from the cell. The work reveals a novel receptor-mediated copper trafficking pathway that retains metal in membrane bound organelles until it is exported from the cell.

  • Copper ions trigger disassembly of Neurokinin B functional amyloid and inhibit de novo assembly.
    Journal of Structural Biology, 2019
    Co-Authors: Bhawantha M. Jayawardena, Mark R. Jones, Yuning Hong, Christopher E. Jones
    Abstract:

    Abstract The formation of amyloid is considered an intrinsic ability of most polypeptides. It is a structure adopted by many neuropeptides and neurohormones during the formation of dense core vesicles in secretory cells, yet the mechanisms mediating assembly and disassembly of these amyloids remain unclear. Neurokinin B is a neuropeptide thought to form an amyloid in secretory cells. It is known to coordinate copper, but the physiological significance of metal binding is not known. In this work we explored the amyloid formation of Neurokinin B and the impact that metals had on the aggregation behaviour. We show that the production of Neurokinin B amyloid is dependent on the phosphate concentration, the pH and the presence of a histidine at position 3 in the primary sequence. Copper(II) and nickel(II) coordination to the peptide, which requires the histidine imidazole group, completely inhibits amyloid formation, whereas zinc(II) slows, but does not inhibit fibrillogenesis. Furthermore, we show that copper(II) can rapidly disassemble preformed Neurokinin B amyloid. This work identifies a role for copper in Neurokinin B structure and reveals a mechanism for amyloid assembly and disassembly dependent on metal coordination.

  • The tachykinin peptide Neurokinin B binds copper(I) and silver(I) and undergoes quasi-reversible electrochemistry: Towards a new function for the peptide in the brain
    Neurochemistry International, 2014
    Co-Authors: Aidan Bradley Grosas, Palraj Kalimuthu, Alison C. Smith, Peter A. Williams, Thomas J. Millar, Paul V. Bernhardt, Christopher E. Jones
    Abstract:

    The tachykinin neuropeptide family, which includes substance P and Neurokinin B, is involved in a wide array of biological functions. Among these is the ability to protect against the neurotoxic processes in Alzheimer's Disease, but the mechanisms driving neuroprotection remain unclear. Dysregulation of metal ions, particularly copper, iron and zinc is a common feature of Alzheimer's Disease, and other amyloidogenic disorders. Copper is known to be released from neurons and recent work has shown that some tachykinins can bind Cu(II) ions, and that Neurokinin B can inhibit copper uptake into astrocytes. We have now examined whether Neurokinin B is capable of binding Cu(I), which is predicted to be available in the synapse. Using a combination of spectroscopic techniques including cyclic voltammetry and magnetic resonance we show that Neurokinin B can bind Cu(I) either directly from added CuCl or by reduction of Cu(II)-bound Neurokinin B. The results showed that the Cu(I) binding site differs greatly to that of Cu(II) and involves thioether coordination via Met2 and Met10 and an imidazole nitrogen ligand from His3. The Cu(I) coordination is also different to the site adopted by Ag(I). During changes in oxidation state, copper remains bound to Neurokinin B despite large changes to the inner coordination sphere. We predict that Neurokinin B may be involved in synaptic copper homeostasis.

Giuseppe Giardina - One of the best experts on this subject based on the ideXlab platform.

  • Nonpeptide tachykinin receptor antagonists. III. SB 235375, a low central nervous system-penetrant, potent and selective Neurokinin-3 receptor antagonist, inhibits citric acid-induced cough and airways hyper-reactivity in guinea pigs.
    Journal of Pharmacology and Experimental Therapeutics, 2002
    Co-Authors: Douglas W. P. Hay, Giuseppe Giardina, William Potts, Don E. Griswold, David C. Underwood, Charles J. Kotzer, Brian Bush, Punam Sandhu, Dave Lundberg, James J. Foley
    Abstract:

    In this report the in vitro and in vivo pharmacological and pharmacokinetic profile of (−)-( S )- N -(α-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide (SB 235375), a low central nervous system (CNS)-penetrant, human Neurokinin-3 (NK-3) receptor (hNK-3R) antagonist, is described. SB 235375 inhibited 125I-[MePhe7]-Neurokinin B (NKB) binding to membranes of Chinese hamster ovary (CHO) cells expressing the hNK-3R (CHO-hNK-3R) with a K i = 2.2 nM and antagonized competitively NKB-induced Ca2+ mobilization in human embryonic kidney (HEK) 293 cells expressing the hNK-3R (HEK 293-hNK-3R) with a K b = 12 nM. SB 235375 antagonized senktide (NK-3R)-induced contractions in rabbit isolated iris sphincter (pA2 = 8.1) and guinea pig ileal circular smooth muscles (pA2 = 8.3). SB 235375 was selective for the hNK-3R compared with hNK-1 ( K i > 100,000 nM) and hNK-2 receptors ( K i = 209 nM), and was without effect, at 1 μM, in 68 other receptor, enzyme, and ion channel assays. Intravenous SB 235375 produced a dose-related inhibition of miosis induced by i.v. senktide in the rabbit (ED50 of 0.56 mg/kg). Intraperitoneal SB 235375 (10–30 mg/kg) inhibited citric acid-induced cough and airways hyper-reactivity in guinea pigs. In mice oral SB 235375 (3–30 mg/kg) was without significant effect on the behavioral responses induced by intracerebral ventricular administration of senktide. Pharmacokinetic evaluation in the mouse and rat revealed that oral SB 235375 was well absorbed systemically but did not effectively cross the blood-brain barrier. The preclinical profile of SB 235375, encompassing high affinity, selectivity, oral activity, and low CNS penetration, suggests that it is an appropriate tool compound to define the pathophysiological roles of the NK-3Rs in the peripheral nervous system. * NKA : Neurokinin A NKB : Neurokinin B CNS : central nervous system NK-1R : Neurokinin-1 receptor NK-2R : Neurokinin-2 receptor NK-3 : Neurokinin-3 NK-3R : Neurokinin-3 receptor PEG : polyethylene glycol CHO : Chinese hamster ovary CHO-hNK-3R : CHO cells stably expressing the human NK-3R CHO-hNK-2R : CHO cells stably expressing the human NK-2R CHO-hNK-1R : CHO cells expressing the human NK-1R HEK : human embryonic kidney HEK 293-hNK-3R : HEK 293 cells stably expressing the human NK-3R HEK 293-mNK-3R : HEK 293 cells transiently expressing the murine NK-3R HEK 293-mNK-2R : HEK 293 cells transiently expressing the murine NK-2R IC50 : concentration of antagonist causing 50% inhibition of agonist response K i : apparent inhibition constant K b : dissociation constant ANOVA : analysis of variance 5-HT : serotonin (5-hydroxytryptamine)

  • 2 phenyl 4 quinolinecarboxamides a novel class of potent and selective non peptide competitive antagonists for the human Neurokinin 3 receptor
    Journal of Medicinal Chemistry, 1996
    Co-Authors: Giuseppe Giardina, James J. Foley, Henry M Sarau, Carlo Farina, Andrew D Medhurst, Mario Grugni, Luca Francesco Raveglia, Dulcie B Schmidt, Roberto Rigolio, Marco Vassallo
    Abstract:

    Pharmacological and molecular biological studies indicate the existence of at least three human tachykinin receptor subtypes, designated Neurokinin-1 (NK-1), Neurokinin-2 (NK-2), and Neurokinin-3 (NK-3),1-3 which belong to the superfamily of G-protein-coupled receptors possessing seven transmembrane domains.4 The endogenous ligands for these receptors constitute a family of small neuropeptides, named tachykinins or Neurokinins, which share the common carboxy-terminal region Phe-X-Gly-Leu-MetNH2. The main mammalian tachykinins, substance P, Neurokinin A (NKA), and Neurokinin B (NKB), interact with all three tachykinin receptors, although there is a defined agonist rank order of potency for NK-1, NK-2, and NK-3 receptors, respectively; for example, for the NK-3 receptor the rank potency order is NKB > NKA > substance P. Over the past few years potent and selective peptide and non-peptide antagonists for the NK-1 and NK-2 receptors have been identified.5-8 These pharmacological tools accelerated the clarification of physiological and pathophysiological roles of these receptors9 and the potential therapeutic indications for NK-1 and NK-2 receptor antagonists.10-13 In contrast to the NK-1 and NK-2 receptor research area, there is limited information on the biology and potential pathophysiological significance of the NK-3 receptor. This was, to a large extent, due to the lack of sufficient potency and selectivity of the peptide NK-3 antagonists described thus far14 and to the absence of non-peptide NK-3 receptor ligands until recently. However, the recent disclosure of the “peptoid” NK-3 antagonist PD 15767215 and the peptidederived PD 16118216 has provided improved reagents for these studies and stimulated the search for more potent and metabolically stable non-peptide NK-3 receptor antagonists. The human NK-3 (hNK-3) receptor mRNA has been detected, using polymerase chain reaction (PCR), to various regions in the central nervous system (CNS) and also, albeit to a lesser extent, in some peripheral tissues, including kidney, placenta, lung, and colon.17 Activation of NK-3 receptors modulates the release of various transmitters in the CNS and periphery,18-20 suggesting that they may have a neuromodulatory role. Recently, (S)-(+)-N-{{3-[1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]prop-1-yl}-4-phenylpiperidin-4-yl}-Nmethylacetamide, SR 142801 (1, Chart 1), was reported as the first potent non-peptide NK-3 receptor antagonist.21,22 Chemically, SR 142801 derives from a constrained analog of SR 48968, a potent NK-2 receptor antagonist (Ki ) 0.51 nM, for displacement of [125I]NKA) in rat duodenum membranes,7 which has moderate affinity for NK-3 receptors (IC50 ) 320 nM, for displacement of [3H]senktide {succinyl-[Asp9MePhe8]SP(6-13)}) in guinea pig cerebral cortex membranes.23 We now report on the discovery of a novel class of potent and selective non-peptide NK-3 receptor antagonistssstructurally unrelated to the piperidine derivatives SR 142801 and SR 48968swhich are based on the 2-phenylquinoline backbone.24 Chemical synthesis (Scheme 1), radioligand binding affinities for the cloned human Neurokinin receptors stably expressed in CHO cell lines (hNKs-CHO),17,25,26 in vitro functional activity in the rabbit isolated iris sphincter muscle preparation (antagonism of senktide-induced contraction),27 and structure-activity relationships (SARs) of the novel † Italy. ‡ USA. § England. © Copyright 1996 by the American Chemical Society