Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Inhibition of NK3 receptor agonist-induced contraction in the rabbit isolated iris sphincter muscle was used to assess the in vitro functional activity of three 2-phenyl-4-quinolinecarboxamides, members of a novel class of potent and selective non-peptide NK3 receptor antagonists. In addition, an in vivo correlate of this in vitro response, namely NK3 receptor agonist-induced miosis in conscious rabbits, was characterized with some of these antagonists. 2. In vitro senktide (succinyl-[Asp9,MePhe8]-substance P (6-11) and [MePhe7]-neurokinin B ([MePhe7]-NKB) were potent contractile agents in the rabbit iris sphincter muscle but exhibited quite different profiles. Senktide produced monophasic log concentration-effect curves with a mean pD2=9.03+/-0.06 and mean nH=1.2+/-0.02 (n=14). In contrast, [MePhe7]-NKB produced shallow log concentration-effect curves which often appeared biphasic (nH=0.54+/-0.04, n=8), preventing the accurate determination of pD2 values. 3. The contractile responses to the NK3 receptor agonist senktide were antagonized in a surmountable and concentration-dependent manner by SB 223412 ((-)-(S)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-ca rboxamide; 3-30 nM, pA2=8.4, slope=1.8+/-0.3, n=4). SB 222200 ((-)-(S)-N-(alpha-ethylbenzyl)-3-methyl-2-phenylquinoline-4-car box amide; 30-300 nM, pA2=7.9, slope=1.4+/-0.06, n=4) and SB 218795 ((-)-(R)-N-(alpha-methoxycarbonylbenzyl)-2-phenylquinoline-4-carboxamide; 0.3 and 3 microM apparent pKB=7.4+/-0.06, n=6). 4. Contractile responses to the NK3 receptor agonist [MePhe7]-NKB in the rabbit iris sphincter muscle were unaffected by SB 218795 (0.3 and 3 microM, n=8). In contrast, SB 223412 (30 and 300 microM n=4) and SB 222200 (0.3 and 3 microM, n=4) inhibited responses to low concentrations (< or = 1 nM), to a greater extent than higher concentrations (> 1 nM) of [MePhe7]-NKB. Furthermore, log concentration-effect curves to [MePhe7]-NKB became steeper and monophasic in the presence of each antagonist. 5. SB 218795 (3 microM, n=4) had no effect on contractions induced by transmural nerve stimulation (2 Hz) or substance P, exemplifying the selectivity of this class of antagonist for functional NK3 receptors over NK1 receptors in the rabbit. 6. In vivo, senktide (1, 10 and 25 microg i.v., i.e. 1.2, 11.9 and 29.7 nmol, respectively) induced concentration-dependent bilateral miosis in conscious rabbits (maximum pupillary constriction=4.25+/-0.25 mm; basal pupillary diameter 7.75+/-0.48 mm; n=4). The onset of miosis was within 2-5 min of application of senktide and responses lasted up to 30 min. Responses to two i.v. administrations of 25 microg senktide given 30 min apart revealed no evidence of tachyphylaxis. Topical administration of atropine (1%) to the eye enhanced pupillary responses to 25 microg senktide. This was probably due to the mydriatic effect of atropine since it significantly increased baseline pupillary diameter from 7.0+/-0.4 mm to 9.0+/-0.7 mm (n=4), thereby increasing the maximum capacity for miosis. Senktide-induced miosis was inhibited by SB 222200 (1 and 2 mg kg[-1], i.v., i.e. 2.63 and 5.26 micromol kg[-1]; maximum inhibition 100%; n=3-4), SB 223412 (0.5 and 1 mg kg[-1], i.v., i.e. 1.31 and 2.61 micromol kg[-1]; maximum inhibition 100%; n=3), SB 218795 (0.5 and 1 mg kg[-1] i.v., i.e. 1.26 and 2.52 micromol kg-1; maximum inhibition 78%; n=3), and the structurally distinct NK3 receptor antagonist SR 142801 ((S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)-4-phenylepipiperidin-4-yl)-N-methylacetamide; 1.5mg kg-1, i.v., i.e. 2.47micromol kg-1, maximum inhibition 92%; n=3). 7. Topical administration of senktide (25microg; 29.7nmol) to the eye induced unilateral miosis in the treated eye only. At this dose there was no significant difference (P<0.05) between pupillary constriction obtained by topical or i.v. senktide, and topically administered atropine had no significant effect on responses to topical senktide (n=4). 8. [MePhe7]-NKB (125, 250 and 500microg, i.v., i.e. 98.31, 196.62 and 393.24nmol, respectively) also induced bilateral miosis in conscious rabbits (maximum pupillary constriction=4.13+/-0.30mm; n=4), but in contrast to in vitro studies this agonist was approximately 100 fold less potent than senktide. [MePhe7]-NKB-induced miosis was inhibited by SB 222200 (5mg kg-1, i.v., i.e. 13.14micromol kg-1; maximum inhibition 69%; n=3). 9. In summary, SB 223412, SB 222200 and SB 218795 are potent and selective antagonists of NK3 receptor-mediated contraction in the rabbit isolated iris sphincter muscle. In addition, NK3 receptor agonist-induced miosis in conscious rabbits is a good in vivo correlate of the in vitro rabbit iris sphincter muscle preparation and appears to be a useful model for characterizing the pharmacodynamic profile and efficacy of structurally distinct NK3 receptor antagonists, such as SB 222200, SB 223412, SB 218795 and SR 142801.
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PMID:In vitro and in vivo characterization of NK3 receptors in the rabbit eye by use of selective non-peptide NK3 receptor antagonists. 935 3

Previous studies in vitro have shown that NK3 receptors exist on primary afferent terminals in rat spinal cord and mediate potentiation of the depolarisation-evoked substance P (SP) release. In the present study we have investigated the role of the NK3 receptor-mediated SP release system in a model of inflammatory pain. Monoarthritis was induced in rats by unilateral injection of complete Freund's adjuvant (CFA); withdrawal latencies to a thermal stimulus were subsequently measured at various times following CFA. The CFA-treated paw displayed hyperalgesia as early as 4 h after CFA injection and hyperalgesia was maintained until day 4 but had disappeared by day 21. The thermal hyperalgesia was associated with an increase in basal SP release from spinal cord synaptosomes. The possible involvement of endogenous neurokinin B acting at NK3 receptors was tested by using SB 223412-A [(S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carbo xamide hydrochloride], a novel, potent (Ki=30 nM) and selective (Ki>10,000 nM for NK1 and NK2 receptors), non-peptidic NK3 receptor antagonist. In vitro SB 223412-A antagonised the potentiation of SP release produced by senktide in spinal cord synaptosomes. Administered systemically to monoarthritic rats (50 mg/kg, p.o., b.i.d., for 4 days), the NK3 receptor antagonist SB 223412-A significantly reduced thermal hyperalgesia and normalised the basal release of SP from spinal cord synaptosomes. The data suggest that neurokinin B acting at NK3 receptors that mediate SP release within the spinal cord play a role in inflammation. These NK3 receptors may represent, therefore, appropriate targets in the therapy of inflammatory pain.
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PMID:NK3 receptor blockade prevents hyperalgesia and the associated spinal cord substance P release in monoarthritic rats. 1066 27

A stepwise chemical modification from human neurokinin-3 receptor (hNK-3R)-selective antagonists to potent and combined hNK-3R and hNK-2R antagonists using the same 2-phenylquinoline template is described. Docking studies with 3-D models of the hNK-3 and hNK-2 receptors were used to drive the chemical design and speed up the identification of potent and combined antagonsits at both receptors. (S)-(+)-N-(1-Cyclohexylethyl)-3-[(4-morpholin-4-yl)piperidin-1-yl]methyl-2-phenylquinoline-4-carboxamide (compound 25, SB-400238: hNK-3R binding affinity, K(i) = 0.8 nM; hNK-2R binding affinity, K(i) = 0.8 nM) emerged as the best example in this approach. Further studies led to the identification of (S)-(+)-N-(1,2,2-trimethylpropyl)-3-[(4-piperidin-1-yl)piperidin-1-yl]methyl-2-phenylquinoline-4-carboxamide (compound 28, SB-414240: hNK-3R binding affinity, K(i) = 193 nM; hNK-2R binding affinity, K(i) = 1.0 nM) as the first hNK-2R-selective antagonist belonging to the 2-phenylquinoline chemical class. Since some members of this chemical series showed a significant binding affinity for the human mu-opioid receptor (hMOR), docking studies were also conducted on a 3-D model of the hMOR, resulting in the identification of a viable chemical strategy to avoid any significant micro-opioid component. Compounds 25 and 28 are therefore suitable pharmacological tools in the tachykinin area to elucidate further the pathophysiological role of NK-3 and NK-2 receptors and the therapeutic potential of selective NK-2 (28) or combined NK-3 and NK-2 (25) receptor antagonists.
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PMID:Stepwise modulation of neurokinin-3 and neurokinin-2 receptor affinity and selectivity in quinoline tachykinin receptor antagonists. 1135 3

Microvascular leakage hypersensitivity is a main component of neurogenic inflammation and of tachykinin effects. The aim of this study was to examine the ability of neurokinin B and of the tachykinin NK(3) receptor agonists, [MePhe(7)]neurokinin B or senktide, to potentiate when given by aerosol the microvascular leakage induced by histamine in guinea-pig airways and to compare their effects to those of tachykinin NK(1) (substance P, [Sar(9),Met(O(2))(11)]substance P) or tachykinin NK(2) (neurokinin A, [betaAla(8)]neurokinin A (4-10)) receptor agonists. Guinea-pigs were pretreated successively for 10 min with aerolized salbutamol and phosphoramidon; 15 min later, they were exposed for 30 min to an aerosolized solution of tachykinin receptor agonists; 24 h later, the animals were anaesthetized and vascular permeability was quantified by extravasation of Evans blue dye. Neurokinin B, [MePhe(7)]neurokinin B and senktide (3 x 10(-6)-3 x 10(-5)M) induced a potentiation of the effects of histamine on the vascular permeability in the trachea and main bronchi. Compared to other tachykinin NK(1) and NK(2) receptor agonists, the order of potency was: senktide>neurokinin B=[Sar(9),Met(O(2))(11)]substance P=[betaAla(8)]neurokinin A (4-10)=[MePhe(7)]neurokinin B>neurokinin A>substance P. The potentiation by [MePhe(7)]neurokinin B of histamine-induced microvascular leakage was abolished by the tachykinin NK(1) receptor antagonist SR140333 ([(S)1-(2-[3-(3,4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)piperidin-3-yl]etyl)-4-phenyl-1-azoniabicyclo[2.2.2]octane, chloride]) or the tachykinin NK(3) receptor antagonists SR 142801 ([(R)-(N)-(1-(3-(l-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl) propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide]) and SB 223412 ([(S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide]). In conclusion, these results suggest that tachykinin NK(3) receptors might be involved in the potentiation of histamine-induced increase in microvascular permeability.
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PMID:Tachykinin NK(3) receptor agonists induced microvascular leakage hypersensitivity in the guinea-pig airways. 1175 53

The aim of the present study was to determine the role of tachykinin in the micturition reflex in guinea pigs. We investigated the effects of tachykinin NK(1) receptor antagonists, GR205171 ([2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-(2S-phenyl-piperidin-3S-yl)-amine), CP99994 ((+), (2R, 3R)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine) and FK888 (N(2)-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl) carbonyl-L-prolyl]-N-methyl-N-phenylmethyl-3-(2-naphthyl)-L-alaninamide), the tachykinin NK(2) receptor antagonist, SR48968 ((+)-N-methyl-[4-(4-acetylamino-4-phenyl piperidino)-2-(3, 4-dichloro-phenyl)butyl] benzamide), and the tachykinin NK(3) receptor antagonist, SB223412 ((S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide) on rhythmic bladder contraction. GR205171 and CP99994 but not SR48968 or SB223412 reduced bladder contraction frequency. FK888 inhibited the frequency very slightly at the highest dose tested. The distribution of tachykinin NK(1) receptor antagonists to the central nervous system after intravenous administration was examined using an ex vivo binding assay. GR205171 was distributed to the brain and spinal cord, but the tachykinin NK(1) receptor antagonist, FK888, was not. These results suggest that tachykinin NK(1) receptors, which are located in the central nervous system, play an important role in micturition in guinea pigs.
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PMID:Contribution of tachykinin receptor subtypes to micturition reflex in guinea pigs. 1452 64

Tachykinins are involved in the central autonomic control of blood pressure. In the present study, we examined the i.c.v. cardiovascular effects of several tachykinin receptor antagonists in awake spontaneously hypertensive rats (SHR, 15 weeks old). Results showed that two tachykinin NK(3) receptor antagonists (R-820: 3-indolylcarbonyl-Hyp-Phg-N(Me)-Bzl and SB 222200: (S)-(-)-N-(alpha-ethylbenzyl)-3-methyl-2-phenylquinoline-4-carboxamide) caused a sustained and dose-dependent reduction of blood pressure when injected i.c.v. but not i.v. The stereoselective anti-hypertensive effect of SB 222200 peaked at 3 h and faded at 6 h post-injection (if injected at 07:00 h) or had a slower onset and peaked at 8 h post-injection (if injected at 13:00 h). The effect of R-820 was maximal at 24 h and lasted up to 48 h post-injection. Both antagonists failed to alter blood pressure in normotensive Wistar-Kyoto rats (WKY) and heart rate was not affected in both strains. The anti-hypertensive effect of SB 222200 was not associated with changes in plasma levels of catecholamines and vasopressin and it remained unchanged in SHR subjected to acute bilateral nephrectomy. In contrast, blood pressure was not affected by tachykinin NK(1) (RP 67580: (+/-) 7,7-diphenyl-2[1-imino-2(2-methoxy-phenyl)-ethyl]perhydroisoindol-4-one(3aR,7aR)) and NK(2) (SR 48968: (S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzamide) receptor antagonists. Data suggest that brain tachykinin NK(3) receptors are implicated in the maintenance of hypertension in SHR. Hence, these receptors may represent promising therapeutic target in the treatment of arterial hypertension.
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PMID:Central anti-hypertensive effect of tachykinin NK3 receptor antagonists in rat. 1475 11

Tachykinin receptor agonists and antagonists were microinjected into the ventral tegmental area (VTA) to study the relative participation of the three tachykinin receptors in cardiovascular regulation in freely behaving rat. Selective agonists (1-100 pmol) for NK1 ([Sar9, Met (O2)11]SP), NK2 ([beta-Ala8]NKA (4-10)) and NK3 (senktide) receptors evoked increases in blood pressure, heart rate (HR) along with behavioural manifestations (face washing, sniffing, head scratching, rearing, wet dog shake). At 1 pmol, NK1 and NK3 agonists did not affect behaviour and blood pressure but only HR. Tachykinin agonists-induced cardiovascular responses were selectively and reversibly blocked by the prior injection of antagonists for NK1 receptors (LY 303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino]propane), 5 nmol), NK2 receptors (SR 48968 ([(S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3,4-dichlorophenyl)butyl]benzamide]), 250 pmol) and NK3 receptors (SB 235375 ((-)-(S)-N-(alpha-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide), 25 nmol). With the exception of the NK2 agonist, most behavioural effects were also blocked by antagonists. Tachykinin agonists-induced cardiovascular responses were inhibited by intravenous (i.v.) treatments with antagonists for D1 dopamine receptor (SCH23390, 0.2 mg kg(-1)) and beta1-adrenoceptor (atenolol, 5 mg kg(-1)) but not for D2 dopamine receptor (raclopride, 0.16 mg kg(-1)). Behavioural responses were blocked by SCH23390 only. The present study provides the first pharmacological evidence that the three tachykinin receptors in the rat VTA can affect the autonomic control of blood pressure and HR by increasing midbrain dopaminergic transmission. This mechanism may be involved in the coordination of behavioural and cardiovascular responses to stress and noxious stimulation.
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PMID:The ventral tegmental area as a putative target for tachykinins in cardiovascular regulation. 1589 9

We evaluated the neuroprotective potential of tachykinin peptides using a model system in which mesencephalic dopaminergic (DA) neurons die spontaneously and selectively as they mature. The three native tachykinins, substance P (SP), neurokinin (NK) A, and NKB afforded substantial protection against DA cell demise. The selective NK1 receptor antagonist [D-Pro9,[spiro-gamma-lactam] Leu10,Trp11]substance P (GR71251) was sufficient in itself to suppress the effect of SP, whereas a cotreatment with GR71251 and the NK3 receptor antagonist (R)-N-[alpha-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide (SB218795) was required to prevent the effects of both NKA and NKB. Consistent with these results, D-Ala-[L-Pro9,Me-Leu8]substance P(7-11) (GR73632), a selective agonist of NK1 receptors and [pro7]-NKB, a selective agonist of NK3 receptors, conferred protection to DA neurons, whereas (Lys3, Gly8-R-gamma-lactam-Leu9)neurokinin A(3-10) (GR64349), which activates specifically NK2 receptors, did not. DA neurons rescued by tachykinins accumulated [3H]DA efficiently, which suggests that they were also totally functional. Neuroprotection by tachykinins was highly selective for DA neurons, rapidly reversed upon treatment withdrawal, and reproduced by but independent of glial cell line-derived neurotrophic factor. Survival promotion by tachykinins was abolished by blocking voltage-gated Na+ channels with tetrodotoxin or N-type voltage-gated Ca2+ channels with omega-conotoxin-MVIIA, which indicates that an increase in neuronal excitability was crucially involved in this effect. Together, these data further support the notion that the survival of mesencephalic DA neurons during development depends largely on excitatory inputs, which may be provided in part by tachykinins.
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PMID:Substance P, neurokinins A and B, and synthetic tachykinin peptides protect mesencephalic dopaminergic neurons in culture via an activity-dependent mechanism. 1607 32

Ghrelin increases electrically evoked, neuronally mediated contractions of rat isolated forestomach, a prokinetic-like activity. Since the nerve type sensitive to ghrelin is unclear, we examined the activity of ghrelin in the presence of antagonists at receptors for the main gastric motor neurotransmitters. Electrical field stimulation (EFS; 5 Hz, 0.5 ms, +/-50 V, 30 s every 3 min) of circular muscle preparations evoked tetrodotoxin 1 microM-sensitive responses, consisting of a small initial contraction followed by a further contraction or more usually, by muscle relaxation. Termination of EFS evoked a large rapidly developing after-contraction. Atropine 1 microM prevented contractions during EFS, increased any relaxations and prolonged the after-contractions. Nomega-Nitro-L-arginine-methyl-ester-hydrochloride (L-NAME) 0.3 mM prevented relaxations during EFS, changing the triphasic response into a monophasic contraction. The tachykinin NK1 and tachykinin NK2 receptor antagonists N-acetyl-L-tryptophan-3,5-bistrifluoromethyl-benzyl-ester (L-732,138 1 microM) and Cyclo[Gln-Trp-Phe-Gly-Leu-CH2N(CH3)-Leu] (MDL-29,913 1 microM) each reduced EFS-evoked relaxations; the latter also reduced the after-contractions. The tachykinin NK3 receptor antagonist (-)-(S)-N-(alpha-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide (SB-235375, 0.1 microM) had no effects. The combination of tachykinin NK(1,2,3) receptor antagonists reduced the after-contractions and abolished relaxations during EFS, replacing this with a contraction. In control tissues, ghrelin 1 microM increased EFS-induced contractions and tended to reduce any relaxations. In the presence of atropine 1 microM, L-NAME 0.3 mM or the tachykinin receptor antagonists (as above), ghrelin 1 microM increased any EFS-induced contraction but in the presence of atropine had no effects on EFS-evoked relaxations. We conclude that EFS evokes responses mediated by acetylcholine, nitric oxide and tachykinins. Ghrelin facilitates both cholinergic and tachykininergic excitatory pathways, consistent with activity within the enteric nervous system and possibly the vagus nerve.
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PMID:The prokinetic-like activity of ghrelin in rat isolated stomach is mediated via cholinergic and tachykininergic motor neurones. 1685 71