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1.
Abstract: Glycine‐9 and leucine‐10 of substance P (SP) are critical for (NK)‐1 receptor recognition and agonist activity. Proψ(Z)‐CH=CH(CH3)‐CONH)Leu (or Met) and Proψ((E)‐CH=CH(CH3)‐CONH)Leu (or Met) have been introduced in the sequence of SP, in order to restrict the conformational flexibility of the C‐terminal tripeptide, Gly‐Leu‐Met‐NH2, of SP. Proψ((Z)‐CH=C(CH2CH(CH3)2)‐CONH)Met‐NH2, with an isobutyl substituent to mimic the Leu side‐chain, was also incorporated in place of the C‐terminal tripeptide. The substituted‐SP analogs were tested for their affinity to human NK‐1 receptor specific binding sites (NK‐1M and NK‐1m) and their potency to stimulate adenylate cyclase and phospholipase C in Chinese Hamster ovary (CHO) cells transfected with the human NK‐1 receptor. The most potent SP analogs [Pro9ψ((Z)CH=C(CH3)CONH)Leu10]SP and [Pro9ψ ((E)CH=C(CH3)CONH)Leu10]SP, are about 100‐fold less potent than SP on both binding sites and second messenger pathways. These vinylogous (Z)‐ or (E)‐CH=C(CH3)‐ or (Z)‐CH=C(CH2CH(CH3)2) moieties hamper the correct positioning of the C‐terminal tripeptide of SP within both the NK‐1M‐ and NK‐1m‐specific binding sites. The origin of these lower potencies is related either to an incorrect peptidic backbone conformation and/or an unfavorable receptor interaction of the methyl or isobutyl group.  相似文献   

2.
Summary This study was initiated to characterize the receptors which mediate the cardiovascular responses elicited by the intrathecal (i. th.) administration of neurokinins (NK) in the conscious freely moving rat. The dose response profile for substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) was determined over 0.065—65 nmol doses of the peptides. After i.th. administration at the T8–T10 thoracic level, only SP elicited a dose dependent pressor response. However, all NK elicited a dose dependent increase in heart rate (HR), and the following rank order of potency was observed: SP > NKA > NKB. SP (6.5 nmol) produced cardiovascular responses markedly greater than an equimolar dose of any of the seven SP fragments which were studied. The C-terminal sequences SP (4-11), [pGlu5]SP (5-11), [pGlu6]SP (6–11), and SP (7–11), as a group were slightly more potent than the N-terminal fragments, SP (1–4), SP (1–7) and SP (1–9) which were almost inactive. The NK-1 receptor selective agonists [Pro9, Met(O2)11]SP and [-Ala4, Sar9, Met(O2)11]SP (4–11), produced pressor and positive chronotropic responses equal to or greater in intensity than SP. With up to 6.5 nmol of the NK-2 receptor selective agonist [Nle10]NKA (4–10), no dose dependent cardiovascular response was produced and the NK-3 receptor selective agonist senktide (succinyl-[Asp6, McPhe8]SP (6–11)), produced neither a cardiac nor pressor response when 6.5 nmol was administered. These results are consistent with the hypothesis that, receptors of the NK-1 subtype mediate the cardiovascular responses evoked by the spinal action of NK. Send offprint requests to R. Couture at the above address  相似文献   

3.
We investigated the role of tachykinin receptor subtypes on secretory responses in the guinea-pig distal colon using Ussing chamber experiments and intracellular recordings from submucosal neurones. Choline acetyltransferase (ChAT) and vasoactive intestinal polypeptide (VIP) were demonstrated in submucosal neurones by immunohistochemistry. In Ussing chamber experiments substance P (SP), the NK-1-receptor agonist [SAR9,Met(O2)11]-SP and the NK-3-receptor agonist (MePhe7)-NKB increased dose-dependently short-circuit currents. The NK-2-receptor agonist (βAla8)-NKA(4–10) had no effect. Responses to 1–100 nM SP, [(SAR9,Met(O2)11]-SP and (MePhe7)-NKB were tetrodotoxin-sensitive but hexamethonium-insensitive. While (MePhe7)-NKB-responses were atropine-sensitive at all concentrations, the atropine sensitivity of the secretory responses to SP and [SAR9,Met(O2)11]-SP dramatically decreased with increasing concentrations. [SAR9,Met(O2)11]-SP and (MePhe7)-NKB effects were blocked by the selective NK-1 and NK-3 antagonists CP-99,994–1 (1 μM) and SR 142801 (1 μM), respectively. Combination of both antagonists blocked the SP-response. SR 142801 also suppressed the response to [SAR9,Met(O2)11]-SP. Desensitization with [SAR9,Met(O2)11]-SP significantly decreased (MePhe7)-NKB-responses but not vice versa. In intracellular recordings 90% of submucosal neurones were activated by both [SAR9,Met(O2)11]-SP and (MePhe7)-NKB as indicated by membrane depolarisation and enhanced spike discharge. These effects were tetrodotoxin-resistant and potentiated by atropine. NK-1- and NK-3-mediated responses occurred equally in ChAT-positive and in VIP-positive neurones. The results suggest the importance of NK-1- and NK-3-receptors on cholinergic and non-cholinergic submucosal neurones for secretory processes in the guinea-pig distal colon. Received: 16 June 1998 / Accepted: 22 September 1998  相似文献   

4.
Summary The effects on mean arterial pressure (MAP) and heart rate (HR) of increasing doses (0.65–65 nmol/kg) of substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and selective agonists for neurokinin receptors were measured after intravenous (i. v.) injection in urethane anaesthetized rats. Neurokinins (NKs) elicited a vasodepressor effect with the following rank order of potency: SP (100%) > NKB (17.5%) > NKA (10%). The two undecapeptide NK-1 selective agonists, [Pro9, Met(O2)11]SP (787%) and [Sar9, Met(O2)11]SP (697%), evoked a significantly (P < 0.05) greater vasodepressor response than SP, while the potency of the octapeptide NK-1 selective agonist [-Ala4, Sar9, Met(O2)11]SP (4–11) (316%) was not significantly different from SP. Conversely, the NK-2 selective agonist NKA (4–10) (<2%) caused only a small effect. The vasodepressor effect elicited by [MePhe7]NKB (112%) and [-Asp4, MePhe7]NKB (4–10) (92%), two NK-3 selective agonists, were not significantly different from that of SP. Senktide (1,095%) is the most potent NK-3 agonist, and is significantly (P < 0.01) more potent than SP. No cross-desensitization, of the vasodepressor response, was observed between NK-1 and NK-3 selective agonists. I. V. injection of 32.5 nmol/kg of NKA, NKA (4–10) and [-Ala4, Sar9, Met(O2)11]SP (4–11) raised HR, while NKB and the NK-3 selective agonists produced a rapid and marked bradycardia. SP and the two undecapeptide, NK-1 selective agonists, produced an initial increase in HR and a latent long-lasting bradycardia. The bradycardia elicited by [Sar9, Met(O2)11]SP (32.5 nmol/kg) was blocked by methylatropine, hexamethonium, indomethacin and by treatment with capsaicin or compound 48/80. Although the bradycardia elicited by [-Asp4, MePhe7]NKB (4–10) (32.5 nmol/kg) was also blocked by hexamethonium, methylatropine, and by bilateral vagotomy, it remained unaffected after indomethacin, or in rats pretreated with either capsaicin or compound 48/80. The drop in MAP produced by the NK-1 and NK-3 agonists were reduced by hexamethonium, methylatropine and bilateral vagotomy (NK-3 agonist), but remained unaffected by indomethacin, capsaicin, and compound 48/80. The tachycardia to NKA (4–10) (65 nmol/kg) was blocked entirely by sotalol or metoprolol and potentiated by hexamethonium. Guanethidine and bilateral adrenalectomy (48 h) failed to affect the tachycardia induced by the agonist, whereas the combination of both treatments abolished the response. Rats sympathectomized with 6-hydroxydopamine (48 h) reduced the increase in HR to NKA (4–10) only at 1 min post-administration. These results support the hypothesis that the vasodepressor action of SP is mediated by the direct activation of NK-1 receptors on vascular endothelium. NKs can accelerate HR by releasing catecholamines through activation of NK-1 and/or NK-2 receptors, on noradrenergic fibers and adrenal chromaffn cells. Furthermore NKs can exert a depressor effect on the cardiovascular system by producing a vagal reflex (Bezold-Jarisch reflex), following either the activation of NK-3 receptors located on capsaicin-insensitive sensory fibers, or by promoting the release of prostaglandins from mast cells (via a non-receptor mechanism) which in turn will stimulate capsaicin-sensitive sensory fibers.  相似文献   

5.
Binding of the tachykinin NK-3 receptor-preferring radioligand [125I] -Bolton-Hunter scyliorhinin II (BHSCYII) was investigated in membranes from guinea-pig ileum muscularis externa with myenteric plexus (MMP). Specific binding for BHSCYII was saturable and reversible. Curvilinear Scatchard plots and biphasic competition data indicate binding to two classes of sites (0.8 nM, 8% of sites; 340 nM, 92% of sites). Competition-binding data was ambiguous with the rank order of potency neuropeptide K (NPK) > substance P (SP) [Sar9,Met(O2)11]-SP [pGlu6,Pro9]SP(6–11) (septide) > neuropeptide (NP) > kassinin physalaemin > neurokinin A (NKA) > SCYII > neurokinin B (NKB). Senktide, eledoisin, [Lys5,MeLeu9,Nle10]-NKA(4–10), CP 96345, RP 67580, MDL 29913, SR 48968 and Gpp[NH]p were ineffective competitors, suggesting a lack of binding to conventional NK-1, NK-2 or NK-3 receptors. Competition curves for 5 agonists could be resolved into two sites, with no competitor showing outstanding affinity. Autoradiographic studies revealed moderate BHSCYII binding to myenteric plexus ganglia, unaffected by co-incubation with CP 96345 or with senktide. These data suggest a component of BHSCYII binding at unusual NPK/SP-preferring sites on ganglia. [Sar9,Met(O2)11]-SP was the most potent contractile agonist of the isolated ileum, followed by SCYII, NPy, senktide and NP, with [Lys5,MeLeu9,Nle10]-NKA(4–10) least potent. Contractions elicited by senktide were entirely neurogenic. Responses to SCYII were partly sensitive to tetrodotoxin, atropine and CP 96345, indicative of action at both neuronal receptors and smooth muscle NK-1 receptors. The NK-2 antagonist SR 48968 did not alter responses to SCYII, [Sar9,Met(O2)11]-SP or senktide. Correspondence to: E. Burcher at the above address  相似文献   

6.
Summary [d-Arg1, dTrp7,9, Leu11]-substance P (spantide) was tested for antagonism against the licking, biting and scratching response induced by various neurokinin (NK) receptor agonists and bombesin (Bom) in mice. When co-administered with substance P (SP) intrathecally, spantide reduced the SP-induced behavioural responses in a dose-dependent manner. The duration of this antagonistic effect was approximately 30 min. Behavioural responses induced by physalaemin (Phy), [pGlu6, l-Pro9]-SP (6–11) (septide), [pGlu6, d-Pro7]-SP (6–11) (d-septide) and eledoisin (Ele) were also dose-dependently decreased by relatively small doses of spantide. Higher doses of spantide were needed to reduce the behavioural responses induced by [Sar9, Met (O2)11]-SP, neurokinin A (NK A) and neurokinin B (NK B). No significant effect of spantide was observed against the behavioural responses elicited by Bom. Pretreatment with naloxone, an opioid antagonist, resulted in a reversible effect on the behavioural reduction of NK-2 and NK-3 receptor agonists produced by spantide. However, the effect of spantide on the NK-1 receptor agonist-induced response was unchanged by naloxone. In homogenates of mouse spinal cord, competition studies confirmed that the binding of the opioid ligand [3H]naloxone was displaced by spantide with a low but measurable affinity. These results suggest that the behavioural response to NK-2 and NK-3 receptor agonists may be partially inhibited by spantide through the activation of opioid system in the mouse spinal cord. Send offprint requests to T. Sakurada at the above address  相似文献   

7.
Three new resins have been developed that allow for the solid phase synthesis of C-terminal peptide N-alkylamides using Boc amino acids, usual side chain protecting groups and hydrogen fluoride cleavage and deprotection. These resins were prepared by reacting the appropriate alkylamine (NH2 CH3, NH2 CH2 CH3, NH2 CH2 CF3) to Merrifield's 1% divinylbenzene cross-linked chloromethylated polystyrene resin. The application of these resins to the synthesis of C-terminal GnRH N-alkylamides illustrates the versatility of this approach. GnRH analogs were tested for their ability to release LH from cultured rat anterior pituitary cells. [D Glu6, Pro9-NHCH2 CH3]-GnRH was synthesized for the first time using the solid phase approach and found to be three times more potent than [D Glu6]-GnRH. Other analogs including [D Trp6, Pro9-NHCH2 CH3]-GnRH, [D Ala6, Pro9-NHCH2 CF3]-GnRH and related peptides were found to be equipotent and to have the same properties (HPLC retention times, amino acid analysis and specific rotation) as the corresponding peptides synthesized using less amenable strategies; yields were equivalent or better than those reported earlier.  相似文献   

8.
In this study, we have used radioligand binding and functional techniques to investigate tachykinin receptors in the small intestine of the cane toad Bufo marinus. The radioligand [125I]Bolton-Hunter [Sar9,Met(O2)11]substance P (selective at mammalian NK-1 receptors) showed no specific binding. Specific binding of [125I]Bolton-Hunter substance P ([125I]BHSP) was saturable, of high affinity (Kd 0.3 nM) and was inhibited by SP (IC50 0.64 nM) > ranakinin < neurokinin A (NKA) $ SP(5–11) $ neuropeptide γ $ scyliorhinin II > scyliorhinin I $ [Sar9]-SP $ neurokinin B < physalaemin < carassin >> SP(7–11) < eledoisin $ SP(4–11) < SP(6–11). Binding was also inhibited by Gpp[NH]p $ GTPγS > App[NH]p, indicating a G-protein coupled receptor. The order of potency of tachykinins and analogues in contracting the isolated lower small intestine was carassin (EC50 1.4 nM) > eledoisin < SP $ physalaemin $ ranakinin > SP(6–11) > scyliorhinin II $ neuropeptide γ > neurokinin B < NKA < scyliorhinin I $ SP(4–11) $ SP(5–11) > [Sar9]SP > SP(7–11). In both studies, the selective mammalian NK-1, NK-2 and NK-3 receptor agonists [Sar9,Met(O2)11]SP, [Lys5,MeLeu9,Nle10]NKA(4–10) and senktide were weak or ineffective. There was a strong positive correlation between the pD2 and pIC50 values for mammalian tachykinins and analogues (r=0.907), but not for the non-mammalian tachykinins, which were all full agonists but variable binding competitors. [Sar9,Met(O2)11]-SP(pD2 5.7) was approximately 25-fold less potent as an agonist than [Sar9]SP, which was itself 25-fold weaker than SP. Responses to SP were significantly reduced (n = 8, P<0.001) by the antagonist [D-Arg1,D-Trp7,9,Leu11]-SP (spantide; 1 μM). Highly selective NK-1 receptor antagonists including CP 99994 and GR 82334 (both 1 μM) were ineffective in both functional and binding studies. Tetrodotoxin (1 μM) did not inhibit contractile responses to SP, NKA and senktide. In summary, this study has shown the presence of one or more tachykinin receptor in the toad intestine. The binding site recognised by [125I]BHSP prefers SP and ranakinin. This toad “NK-1-like receptor” differs from the mammalian NK-1 receptor in having a low affinity for all mammalian NK-1 selective ligands, including antagonists. For some non-mammalian peptides, their high potency as contractile agonists relative to their poor binding affinity suggests the existence of other tachykinin receptors in the toad small intestine. Received: 2 September 1997 / Accepted: 26 March 1998  相似文献   

9.
Solution conformation of cyclo(Gly1-His2-Phe3-Arg4-Trp5-Gly6) and its d -Phe analog corresponding to the message sequence [Gly-α-MSH5-10] of α-MSH has been studied by 1D and 2D proton magnetic resonance spectroscopy in dimethyl sulfoxide (DMSO)-d6 solution and in a DMSO-d6/H2O cryoprotective mixture. The NMR data for both the analogs in solution at 300 K cannot be interpreted based on a single ordered conformation, as evidenced by the broadening of only -NH resonances as well as the temperature coefficients of the amide protons. An analysis of the nuclear Overhauser effect (NOE) cross-peaks in conjunction with temperature coefficient data indicates an equilibrium of multiple conformers with a substantial population of particular conformational states at least in the d -analog. The molecular dynamics simulations without and with NOE constraints also reveal numerous low-energy conformers with two γ-turns, a γ-turn and a β-turn, two β-turns, etc. for both the analogs. The observed NMR spectra can be rationalized by a dynamic equilibrium of conformers characterized by a γ-bend at Gly6, two γ-bends at Phe3 and Gly6 and a conformer with a single β-turn and a γ-bend for the l -Phe analog. On the other hand, a conformation with two fused β-turns around the two tetrads His2-d -Phe3-Arg4-Trp5 and Trp5-Gly6-Gly1-His2 dominates the equilibrium mixture for the d -Phe analog. For the d -Phe analog, the experimentally observed average conformation is corroborated by molecular dynamics simulations as well as by studies in cryoprotective solvent.  相似文献   

10.
Four analogs of human β-endorphin (βh-EP) have been synthesized: [Gly31]-βh-EP-Gly-NH2, [CH3(CH2)4NH312]-βh-EP, [Gly31]-βh-EP-Gly-Gly-NH2, and [Gln8, Gly31]-βh-EP-Gly-Gly-NH2. All are more active than βh-EP in an opiate receptor binding assay. Stepwise extension at the COOH-terminus shows a progressive increase in binding activity. The last analog, which combines extension at the COOH-terminus with elimination of the remaining anionic charge in βh-EP, is nine times more active than the parent molecule.  相似文献   

11.
Summary The effects on plasma extravasation of three increasing doses from 6.5 pmol to 650 nmol/kg of substance P (SP), SP fragments, neurokinin A (NKA), neurokinin B (NKB) and selective agonists for neurokinin receptors were assessed in three cutaneous tissues (skin of hind paws, dorsal skin and ears) by intravenous (i.v.) administration in the pentobarbitone anaesthetized rat. Dose-dependent increases in plasma extravasation were observed with the following rank orders of potency (SP > NKA > NKB) for neurokinins and (SP > [p-Glu6]SP(6–11) > SP(4–11) > [p-Glu5]SP(5–11) > SP(7–11)) for C-terminal SP fragments. The metabolically stable SP analogue [p-Glu5, McPhe8, Sar9]SP(5–11) was slightly more potent than [p-Glu5]SP(5–11). The N-terminal fragments SP(1–4), SP(1–7) and SP(1–9) were inactive up to 650 nmol/kg. The NK-1 receptor selective agonists [Sar9, Met(O2)11]SP and [-Ala4, Sar9, Met (O2)11]SP(4–11) were more potent than the NK-2 ([Nle10]NKA(4–10)) and NK-3 ([MePhe7]NKB and -Asp4, McPhe7NKB(4–10)) receptor selective agonists.Plasma extravasation induced by SP (6.5 nmol/kg) was unchanged in the presence of atropine, methysergide, diphenhydramine or during the i.v. and intra-arterial (i.a.) infusion of d-Arg0[Hyp3. d-Phe7]BK, an antagonist of bradykinin. Plasma extravasation induced by SP and [Sar9, Met(O2)11]SP was significantly reduced by indomethacin while that induced by NKA, NKB, [-Ala4, Sar9, Met(O2)11]SP(4–11), SP(4–11) and [p-Glu6]SP(6–11) was unaffected by the cyclooxygenase inhibitor. Compound 48/80 (0.75 mg/kg), histamine (10 mg/kg) and 5-HT (10 mg/kg) caused an incrase in plasma extravasation, only the effect of compound 48/80 was abolished by indomethacin. Pretreatment with compound 48/80 prevented its own action on plasma extravasation and significantly reduced that induced by 6.5 nmol/kg of SP.These results rule out the involvement of acetylcholine (muscarinic receptors), 5-HT (5-HT1 and 5-HT2 receptors), histamine (H1 receptors) and kinins (B2 receptors) in the response to SP and indicate that the two positively charged amino acids (Arg, Lys) at the N-terminal end of the SP molecule are essential to trigger the release of prostaglandins from mast cells. This mechanism is responsible for the indirect effect of SP and related peptides on capillary permeability and does not appear to be mediated by a selective SP receptor. In addition, neurokinins may increase capillary permeability by direct activation of a NK-1 receptor type on the vascular endothelium. Send offprint requests to R. Couture at the above address  相似文献   

12.
Purpose Substance P (SP; NH3+-Arg+-Pro-Lys+-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2) belongs to a group of neurokinins that are widely distributed in the central nervous system and peripheral nervous system. The biological effects mediated by SP in the central nervous system include regulation of affective behavior, emesis, and nociception. Many of these actions are believed to be the result of the binding of SP to the neurokinin-1 (NK-1) receptor and subsequent transport across the blood–brain barrier (BBB). The objective of the study was to investigate the involvement of the NK-1 receptor in the permeation of SP across the BBB. Methods Transport of 3H SP (1–13 nM) was investigated using BBMEC monolayers grown on polycarbonate membranes mounted on a Side-bi-Side™ diffusion apparatus. 3H SP samples were analyzed by scintillation spectrometry. Liquid chromatography-tandem mass spectrometry was used to monitor the transport at higher concentrations (micromolar). Results SP transport across BBMEC monolayers was found to be saturable (Km = 8.57 ± 1.59 nM, Vmax = 0.017 ± 0.005 pmol min−1 mg−1 protein) in the concentration range of 0–13 nM. Significant (p < 0.05) decline in 3H SP permeation was observed in the presence of unlabeled SP and at 4°C, indicating that the transport process is carrier-mediated. High-performance liquid chromatography analysis showed no significant metabolism of 3H SP in either the donor or receiver chambers. 3H SP transport was inhibited by 2–11 SP (p < 0.05) but not by any other fragments, indicating that both the C- and N-terminal regions are essential for molecular recognition by the receptor. Endocytic inhibitors (chloroquine, phenylarsine oxide, monensin, and brefeldin) did not inhibit SP transport, suggesting the involvement of a nonendocytic mechanism in SP permeation. Pro9 SP, a high-affinity substrate for the NK-1 major subtype receptor, significantly (p < 0.05) inhibited the transport of SP. However, Sar9Met(O2)11 SP, a high-affinity substrate for the NK-1 minor subtype receptor, septide, and neurokinin A, inhibitors of NK-1 and neurokinin-2 (NK-2) receptors, respectively, did not produce any inhibition of SP transport. Western blot analysis confirmed the presence of the NK-1 receptor in BBMEC monolayers. Conclusions The above results provide functional and molecular evidence for the existence of a carrier-mediated mechanism in the transport of SP across the BBB. The effects of specific inhibitors and the results of Western blot analyses demonstrate the involvement of the NK-1 receptor in the transport of SP across the BBB.  相似文献   

13.
  1. The presence of tachykinin NK1 receptors have been shown in the epithelium and smooth muscle of guinea-pig airways. Previous data showed that substance P (SP), and the NK1 receptor agonist, [Sar9, Met (O2)11]-SP, relax guinea-pig tracheal tube preparations by stimulation of epithelial NK1 receptors and via nitric oxide (NO) release. However, the selective tachykinin NK1 receptor agonist, septide, was unable to produce this effect. The aim of the present study was to investigate the ability of a series of SP analogues to stimulate NK1 receptors of guinea-pig airway epithelium.
  2. Isometric tension was recorded in isolated tracheal tube preparations in which compounds were administered intraluminally in the presence of phosphoramidon, indomethacin (both 1 μM) and the tachykinin NK2 receptor antagonist, SR 48,968 ((S)-N-methyl N-(4-acetyl-amino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl)benzamide) (0.1 μM). Cumulative concentration-response curves were obtained in preparations under resting tone or in preparations precontracted with acetylcholine (ACh, 10 μM).
  3. Contractile responses to low concentrations (0.1–10 nM) of substance P (SP) and the selective agonist of NK1 receptors, [Pro9]-SP, in non precontracted tracheae were higher in preparations pretreated with the NO-synthase inhibitor, NG-monomethyl L-arginine (L-NMMA, 100 μM) than in preparations pretreated with its inactive enantiomer D-NMMA (100 μM). Tracheal tube preparations precontracted with ACh and pretreated with D-NMMA were relaxed by low concentrations of SP and [Pro9]-SP (0.1–10 nM). In contrast, after pretreatment with L-NMMA, SP and [Pro9]-SP contracted tracheae at all the concentrations tested.
  4. Concentration-response curves to the NK1 receptor agonists, SP methyl ester, [Apa9–10]-SP and [pGlu6] SP (6–11) obtained in non-precontracted tracheae were similar in the presence of either D-NMMA or L-NMMA. SP methyl ester, [Apa9–10]-SP and [pGlu6] SP (6–11) did not produce any relaxation, but instead, cause contractions in tracheal tube preparations precontracted with ACh and pretreated with D-NMMA. Concentration-response curves produced by all these agonists were similar in preparations precontracted with ACh and pretreated with L-NMMA or D-NMMA.
  5. In guinea-pig tracheal tube preparations two groups of NK1 receptor agonists can be distinguished: one group, including [Pro9]-SP, stimulator epithelial NK1 receptors, the other group, including SP methyl ester, [Apa9–10]-SP and [pGlu6] SP (6–11), does not. One possible explanation for these findings and for the existence of compounds with a peculiar ‘septide-like'' pharmacological profile in the guinea-pig trachea could be the recently proposed phenomenon referred to as ‘agonist-directed receptor trafficking''.
  相似文献   

14.
The conformational analysis of three cyclic hexapeptides is presented. Cyclo-(-Gln6-Trp7-Phe8-Gly9-Leu10-d -Met11-) (1) and cyclo-(-Gln6-Trp7-Phe8-Gly9-Leu10-Met11-) (2) are NK-2 antagonists in the hamster trachea assay, whereas cyclo-(-Gln6-Trp7-Phe8-(R)-Gly9-[ANC-2]Leu10-Met11-) (3), where Gly9[ANC-2]Leu10 represents (2S)-2-((3R)-3-amino-2-oxo-1-pyrrolidinyl)-4-methylpentanoyl, is inactive as agonist and antagonist in this assay. In DMSO, the NMR results cannot be interpreted as being consistent with a single conformation. However, the combined interpretation of results from NMR spectroscopy, restrained molecular dynamics simulations with application of proton–proton distance information from ROESY spectra, and pharmacological results leads to a reduced number of conformational domains for each peptide, which can be compared with each other and may be classified as responsible for their biological activity. Trying to match the conformational domains approximately with regular β- and γ-turns, we find a γn-turn at the position of the methionine occuring in all peptides. For the active peptides 1 and 2 we arrive at an inverse γi-turn at Phe8, and βI′- or βII-turns with Gly9 and Leu10 at the corner positions, these β-turns having a similar topology with respect to the linking peptide unit. Other conformational domains common to only 1 and 2 support their classification as responsible for the biological activity.  相似文献   

15.
Analogues of [Orn6]-SP6-11 have been synthesized in which the methionyl residue is replaced by glutamine γ-carboxamide substituted derivatives. These analogues where tested in three in vitro preparations representative of NK-1, NK-2 and NK-3 receptor types. Substitution of the SCH3 group of the Met11 side chain by CONHCH3, CON(CH3)2, CONHPh and CONCH3Ph groups results in analogues which are full agonists in NK-1 and NK-2 preparations with the exception of the Glu[N(CH3)2]11 and the Glu(NHCH3)11 analogues, which are partial agonists at NK-1 and NK-2 receptors respectively. The Glu(NHCH3)11 analogue shows selectivity for the NK-1 receptor type and is equipotent to the Glu(NCH3Ph)11 analogue in the same receptor type. The latter analogue is 2.84 times more potent than the parent hexapeptide in the NK-2 preparation. The Glu(NHPh)11 analogue is a full agonist in the NK-3 preparation and equipotent to the parent hexapeptide, in contrast to the other analogues in which Met has been replaced by glutamine γ-carboxamide substituted residues. It is concluded that for NK-1 receptor type the lipophilic character of Met11 side chain is not a determining factor for activity but it is an important factor for activity in the NK-2 receptor type and has a stronger effect when a phenyl group is present, thus leading to analogues which are full agonists and more potent than the parent hexapeptide.  相似文献   

16.
Four analogs of the opioid peptide human β-endorphin (βh-EP) have been synthesized: [d -Lys9,Phe27,Gly31]-βh-EP, [d -Phe18,Phe27,Gly31)-βh-EP, [d -Thr2,d -Lys9,Phe27,Gly31]-βh-EP, and [d -Thr2,d -Phe18,Phe27,Gly31]-βh-EP. All are practically indistinguishable from βh-EP in the guinea pig ileum assay. All show diminished analgesic potency in the mouse tail-flick assay.  相似文献   

17.
The folded structure induced by the N-aminoproline residue (the hydrazino analogue of proline, denoted hPro) in the Boc-Gly1-hPro2-Gly3-NHiPr hydrazino tripeptide has been characterized in the solid state by X-ray diffraction, and compared to the usual βII-turn structure in the Boc-Gly1-Pro2-Gly36-NHiPr cognate tripeptide. It is stabilized by a bifurcated hydrogen bond in which (Gly3)NH interacts with both (Gly1)CO and (hPro2)Nx. This conformation is retained in CH2Cl2 and CHC13 solutions, and allows an overall folded conformation of the hydrazino tripeptide in which (iPr)NH is hydrogen-bonded to (Boc)CO. The hPro α-hydrazino acid residue appears to promote a local folded structure, and might behave as a β-turn mimic. © Munksgaard 1994.  相似文献   

18.
1 The aim of this study was to characterize the tachykinin receptors involved in producing plasma protein extravasation and contractile responses of the guinea-pig oesophageal sphincter. 2 In anaesthetized guinea-pigs, the selective tachykinin NK-1 receptor agonist [Sar9,Met(O2)11]substance P produced plasma protein extravasation (PPE) which was not affected by the treatment with the tachykinin NK-2 receptor antagonist MEN 10627 (1 μmol kg??1 i.v.) or the histamine H1-receptor antagonist, diphenhydramine (34.5 μmol kg??1 i.v.). However, the [Sar9,Met(O2)11]substance P-induced PPE was blocked by the previous administration of the peptide tachykinin NK-1 receptor antagonist FK 888 or by the non-peptide antagonist SR 140333, yielding ED50 values of 1.1 ± 0.2 and 0.01 ± 0.004 μmol kg??1 i.v., respectively. 3 The tachykinin NK-2 or NK-3 receptor agonists [β-Ala8]neurokinin A (4–10) or [MePhe7]neurokinin B, respectively, produced a weak PPE at high doses. The effect of [MePhe7]neurokinin B-induced PPE was inhibited by SR 140333. 4 In the guinea-pig isolated oesophageal sphincter, [Sar9,Met(O2)11]substance P did not exert any contractile effect up to 10 μm . The selective tachykinin NK-2 receptor agonist ([β-Ala8]neurokinin A (4–10), produced concentration-dependent contractions (pD2 = 7.6 ± 0.03) which were inhibited by the selective tachykinin NK-2 receptor antagonist, MEN 10627 (pA2 = 8.6 ± 0.1). Also, the tachykinin NK-3 receptor selective agonist [MePhe7]neurokinin B induced concentration-dependent contractile responses, but these responses were inhibited by MEN 10627. 5 Altogether, these data indicate that the stimulation of tachykinin NK-1 receptor produces a vascular inflammatory response, while activation of tachykinin NK-2 receptors mediate the contraction of the guinea-pig oesophageal sphincter.  相似文献   

19.
Abstract: Analogues of GnRH have been widely used in oncology and gynaecology to induce reversible chemical castration. In addition to the classic hypophysiotropic action of GnRH, it has been shown that many malignant cells, such as breast cancer cells, secrete GnRH and express the GnRH receptor/s. In order to study the effect of modifications in position 3 and 6 of GnRH on both pituitary binding affinity and breast cancer cell proliferation, we synthesized eight new GnRH analogues. All GnRH analogues lacked the carboxy–terminal Gly10–amide of GnRH and an ethylamide residue was added to Pro9. Gly6 was substituted by α,α‐dialkyl amino acids (Aib: α‐aminoisobutyric acid, Deg: diethylglycine) and Trp3 by D–Trp, D‐ and L‐1,2,3,4,‐tetrahydro‐isoquinoline‐3‐carboxylic acid (Tic). During competition binding experiments in mouse anterior pituitary αT3‐1 cells, [Aib6,desGly10]GnRH‐NHEt bound to the GnRH receptor with IC50 values comparable to those of parent hormone in contrast to the analogues substituted at position 3 . However, [L‐Tic3,Deg6,desGly10]GnRH‐NHEt had high pituitary binding affinity. With the exception of GnRH and [Aib6,desGly10]GnRH‐NHEt, all GnRH analogues significantly inhibited the proliferation of human breast cancer cells (MCF‐7); higher inhibitory effect was observed for analogues modified at position 3 . Results show differential impact of the modifications on the binding affinity to the GnRH receptor in mouse pituitary cells and on the inhibition of human breast cancer cell proliferation and provide insight into structure‐activity relationship of GnRH in different biological systems.  相似文献   

20.
Summary Neurokinin A, neurokinin B and substance P caused concentration-related contractions of rabbit isolated aorta with pD2 values of 8.1, 6.9 and 6.0, respectively. [D-Pro2, D-Trp7,9]-substance P, a competitive tachykinin antagonist, had pA2 values of 5.3 against neurokinin A, 5.1 against neurokinin B and 5.2 against substance P indicating that tachykinin receptors mediated responses to the agonists. [pGIu5,MePhe8,-McGly9]-substance P 5–11 (DiMe-C7), senktide and septide did not contract the aorta. It is concluded that of the known tachykinin receptors smooth muscle of the rabbit isolated aorta contains only the NK-2 type. Send offprint requests to J. W. Constantine at the above address  相似文献   

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