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. In many species, both NK1 and NK2 tachykinin receptors appear to be important in mediating the contraction of airway smooth muscle. We have examined the distribution and characterization of receptors for tachykinins in rabbit airways using functional length tension studies, autoradiography and radioligand binding studies. 2. Contractile responses to tachykinins were elicited in four different areas of the respiratory tree--trachea, and three progressively more distal areas of the right bronchus. The NK2 receptor-preferring agonists, neurokinin A (NKA), neuropeptide gamma (NP gamma) and the NK2-selective [Lys5 MeLeu9, Nle10]-NKA(4-10) [NKA (4-10) analogue] produced similar contraction in all four areas. Substance P (SP) and the NK1-selective [Sar9,Met(O2)11]-SP (Sar-SP) exhibited a marked location-dependence in the magnitude of contraction, producing minimal contraction in the trachea and more proximal bronchi with contractions becoming progressively larger in the more distal airways. Senktide (which is selective for the NK3 receptor) produced negligible contraction in all areas. 3. The NK2-selective antagonist, MDL29,913, was a weak antagonist of NKA and NKA(4-10) analogue. At a concentration of 2 microM, it produced a small but significant shift in the response curve to NKA and a greater shift (8 fold) in the curve to NKA(4-10) analogue, but it had no effect on responses to Sar-SP. The non peptide NK1 receptor antagonist, CP-96,345, was also unexpectedly weak in this preparation. The pD2 value for Sar-SP was decreased 27 fold by CP-96,345 at a concentration of 1 microM, without alteration in the maximum response.4. Autoradiographic binding sites to ['251I]-NKA were sparse over smooth muscle in proximal airway preparations and markedly increased in density in the more distal airways. There was negligible binding over vascular smooth muscle and epithelium.5. Radioligand binding studies revealed binding to ['251I]-NKA which was 82% specific. The order of potency for inhibition of ['251I]-NKA binding was SP> = Sar-SP> NKA = NPy>CP-96,345> NKA(4-10) analogue >NKB>>>MEN 10207 (the NK2 subtype selective antagonist) >MDL 29,913> senktide. This profile indicates binding predominantly to NK, receptors.6. These results suggest that there are at least two types of tachykinin receptors in rabbit airways, a population of NK, receptors, the density of which is greatest in the periphery and, in addition, NK2 receptors which are uniformly distributed throughout the airways. These receptors have unusual characteristics in that the NK, antagonist, CP-96,345 and the NK2 antagonist, MDL 29,913 respectively exhibited only weak potency.
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PMID:Tachykinin receptors in rabbit airways--characterization by functional, autoradiographic and binding studies. 138 14

We have examined the effects of intrathecally (i.t.) administered CP-96,345, a non-peptide NK1 receptor ligand, on the spinal nociceptive flexor reflex and on the facilitation of this reflex evoked by i.t. substance P (SP), neurokinin A (NKA) and electrical conditioning stimulation of cutaneous C-afferents. CP-96,345 i.t. at 24 pmol-2.4 nmol had no significant effect on flexor reflex excitability. At the highest dose tested (24 nmol), CP-96,345 caused a brief facilitation of the flexor reflex, which was similar to the effect of the vehicle used at this drug concentration. CP-96,345 did not depress the flexor reflex at any dose. In rats with chronically implanted i.t. catheters, CP-96,345 at 24 nmol caused neither motor impairment nor morphological damage to the spinal cord. Pretreatment with CP-96,345 dose dependently and similarly antagonized facilitation of the flexor reflex induced by 7 pmol i.t. SP or by a 20-s, 1-Hz conditioning stimulus train applied to cutaneous C-fibers in the sural nerve innervation area. The vehicle had no effect. The antagonistic effect of CP-96,345 on the SP- and C-fiber reflex facilitation induced by conditioning stimulation became maximal only 20-30 min after the i.t. injection and lasted 3-4 h at the highest dose. CP-96,345 did not significantly block the facilitatory effect of 7 pmol i.t. NKA on the flexor reflex. These results demonstrate that CP-96,345 is a potent, long-lasting and selective antagonist of SP in rat spinal cord. Furthermore, facilitation of the flexor reflex (central sensitization) induced by conditioning stimulation of cutaneous C-afferents is mediated by NK1 tachykinin receptors, but the NK1 receptor may not be involved in the transmission of the flexor reflex. CP-96,345 is thus useful in experimental studies of the role of SP in the central nervous system.
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PMID:Intrathecal CP-96,345 blocks reflex facilitation induced in rats by substance P and C-fiber-conditioning stimulation. 138 60

To identify the tachykinin receptor subclass involved in the central cardiovascular and behavioral actions of substance P (SP), we compared the central actions of SP with those of neurokinin A (NKA) and senktide in conscious chronically instrumented rats. Intracerebroventricular (i.c.v.) injection of SP (an NK1 agonist) and NKA (an NK2 agonist) increased mean arterial pressure (MAP) and heart rate (HR) dose dependently and these cardiovascular responses were associated with the behavioral responses, comprising excessive grooming and exploring. Both peptides were equipotent to produce the cardiovascular and the behavioral responses. Senktide (a highly selective NK-3 agonist), injected i.c.v. increased the HR markedly. The behavioral response, 'wet dog shakes', was observed most frequently after senktide and was dissociated from the HR response. Pretreatment with a peripheral NK-1-selective antagonist, L-668,169, attenuated the NKA-induced cardiovascular and behavioral responses but not the SP-induced responses. However, pretreatment with a peripheral NK-2-selective antagonists, L-659,877, attenuated the SP-induced responses but not the NKA-induced responses. These results suggest that the central cardiovascular and behavioral actions of SP and NKA are mediated by different subclasses of receptors and that the receptor subclasses which are specific for the central nervous system differ from those which mediate the peripheral actions of the two tachykinins.
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PMID:Identification of the central tachykinin receptor subclass involved in substance P-induced cardiovascular and behavioral responses in conscious rats. 138 76

The nonpeptide substance P receptor antagonist CP-96,345 was found to displace binding to Ca2+ channel binding sites labelled with either [3H]desmethoxyverapamil or [3H]diltiazem and to enhance [3H]nitrendipine binding. Unlike the substance P receptor antagonist activity of CP-96,345, these effects on Ca2+ channel binding sites were neither stereoselective nor species-dependent. It is concluded that CP-96,345 may act as an antagonist of L-type Ca2+ channels in addition to being a potent NK1 receptor (substance P) antagonist.
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PMID:The substance P receptor antagonist CP-96,345 interacts with Ca2+ channels. 138 77

Substance P and selective neurokinin receptor agonists have been tested for their ability to induce shape change in rabbit platelets. Substance P and the NK1 receptor agonist Ac [Arg6,Sar9,Met(O2)11]-substance P (6-11) induced shape change (EC50 = 3 and 6 nM, respectively), whereas the selective NK2 agonist [Nle10]-Neurokinin A (4-10) and the selective NK3 agonist [MePhe7]-Neurokinin B did not show any effect. Moreover, the specific NK1 receptor antagonist CP-96,345 selectively and dose-dependently counteracted the effect of substance P or of the NK1 receptor agonist (IC50 = 2 and 0.8 nM, respectively), whereas the selective NK2 receptor antagonist, SR 48968, had no effect. Unlike for serotonin or low doses of ADP, epinephrine did not allow substance P or the NK1 receptor agonist to become a proaggregating substance. These data therefore show that the NK1 receptor is solely involved in the neurokinin-induced shape change of rabbit platelets.
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PMID:The NK1 receptor is involved in the neurokinin-induced shape change of rabbit platelets. 138 16

The regulation of neostriatal cholinergic function by tachykinins (TKs) has been studied by measuring endogenous ACh released from rat neostriatal slices. Septide (SEP; a highly selective substance P analog), neurokinin A (NKA), and neurokinin B (NKB) elicited endogenous ACh release in a concentration-dependent manner. The rank order in potency was the following: NKB (EC50 approximately 0.5 nM) greater than NKA (EC50 approximately 7 nM) greater than SEP (EC50 approximately 12 nM). Spantide (SPA) was less effective (39% inhibition) than [D-Arg6, D-Trp7,9, N-Methyl-Phe8]-substance P fragment 6-11 (53% inhibition) at antagonizing ACh release evoked by SEP and NKA. Smaller doses of the antagonists inhibited the effects of SEP compared to NKA, and the effects of NKB could only be antagonized by SPA. These findings suggest the involvement of the three neurokinin (NK) receptors in ACh release evoked by TKs with the following rank order: NK3 greater than NK2 greater than NK1. 6-Hydroxydopamine lesions of nigrostriatal neurons and tetrodotoxin (TTX) intoxication of striatal tissue revealed two different patterns of regulation of cholinergic function by TKs. On the one hand, SEP and NKA evoked ACh release, independently of the nigrostriatal dopaminergic system, by acting on NK1 and NK2 receptors that are probably localized on the somatodendritic field of cholinergic neurons receiving substance P terminals. On the other hand, dopaminergic terminals seem to regulate NKB neurons that modulate cholinergic neurons, because NKB-evoked ACh release decreased by 24% in the denervated striata. In addition, TTX partially blocked (50%) ACh release evoked by NKB, suggesting that NKB acts on NK3 receptors at both the nerve terminals and the somatodendritic field of cholinergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neurokinin receptors differentially mediate endogenous acetylcholine release evoked by tachykinins in the neostriatum. 165 75

1. The classification of tachykinin receptors in the guinea-pig trachea has been investigated. This was of interest because, from previous studies, it was not clear whether the guinea-pig trachea contains either a mixture of NK1 and NK2 receptors or, alternatively, a single type of novel tachykinin receptor. 2. In the present study, the guinea-pig trachea was contracted by tachykinin agonists selective for NK1 receptors (substance P methylester (SPOMe) and GR73632) or NK2 receptors (GR64349) but not NK3 receptors (senktide). 3. Against SPOMe and GR73632, the NK1 antagonist, GR71251, behaved as a reversible competitive antagonist having apparent affinity (pKB 7.05 vs SPOMe) consistent with action at NK1 receptors. GR71251 (3 microM) did not antagonize responses to GR64349. 4. The NK2 antagonists L-659,877 and Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH2 (R396) antagonized GR64349 although only R396 appeared to behave competitively (pKB 5.73). Neither L-659,877 (30 microM) nor R396 (30 microM) blocked responses to SPOMe. 5. For L-659,877 and R396, comparison was made between activity in guinea-pig trachea and in preparations known to contain tachykinin receptors predominantly of the NK2 type. In the rabbit trachea, both L-659,877 and R396 had effects similar to those in guinea-pig trachea. In contrast, in the rat colon muscularis mucosae, both L-659,877 and R396 appeared to behave competitively with pKB values against GR64349 of 7.83 and 6.90 respectively. 6. It is concluded that in guinea-pig trachea, contractile responses can be induced by activation of both NK1 and NK2 receptors. The present data are discussed with reference to the proposed existence of subtypes of the NK2 receptor.
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PMID:Receptors mediating tachykinin-induced contractile responses in guinea-pig trachea. 165 74

An extract of the whole brain of the frog Rana ridibunda contained high concentrations of substance P-like immunoreactivity, measured with an antiserum directed against the COOH-terminal region of mammalian substance P and neurokinin B-like immunoreactivity, measured with an antiserum directed against the NH2-terminus of neurokinin B. The primary structure of the substance P-related peptide (ranakinin) was established as: Lys-Pro-Asn-Pro-Glu-Arg-Phe-Tyr-Gly-Leu-Met-NH2. Mammalian substance P was not present in the extract. The primary structure of the neurokinin B-related peptide was established as: Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2. This amino acid sequence is the same as that of mammalian neurokinin B. Ranakinin was equipotent with substance P and [Sar9,Met(O2)11]substance P in inhibiting the binding of 125I-Bolton-Hunter-[Sar9,Met(O2)11]substance P, a selective radioligand for the NK1 receptor, to binding sites in rat submandibular gland membranes (IC50 1.6 +/- 0.3 nM; n = 5). It is concluded that ranakinin is a preferred agonist for the mammalian NK1 tachykinin receptor subtype.
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PMID:Ranakinin: a novel NK1 tachykinin receptor agonist isolated with neurokinin B from the brain of the frog Rana ridibunda. 165 33

The affinity of the non-peptide antagonist CP-96,345 for tachykinin NK1 receptors has been estimated in a range of species by use of both radioligand binding and functional assays. CP-96,345 was 30-120 fold less active at NK1 receptors in rat and mouse than in the other species examined, including man. These results demonstrate the existence of species variations in NK1 receptors.
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PMID:Investigation into species variants in tachykinin NK1 receptors by use of the non-peptide antagonist, CP-96,345. 166 29

1. The interaction at tachykinin receptors of a series of novel cyclic hexapeptides has been examined by use of radioligand binding assays (NK1 and NK3 sites in rat cortex, NK2 sites in hamster urinary bladder) and functional pharmacological assays (guinea-pig ileum, rat vas deferens and rat portal vein for NK1, NK2 and NK3 receptors, respectively). 2. The compounds cyclo(GlnTrpPhe(R)Gly[ANC-2]LeuMet) (L-659,837) and cyclo(GlnTrpPheGly-LeuMet) (L-659,877) were powerful and selective displacers of NK2 binding (pIC50 6.9 and 8.0, respectively), and were competitive antagonists of responses to stimulation of NK2 receptors in rat vas deferens (pKB for antagonism of responses to eledoisin 6.7 and 8.1, respectively). Responses in the NK1 and NK3 pharmacological assays were blocked only weakly, if at all. 3. In the longitudinal muscle of the small intestine of the rat, responses to stimulation of the putative NK2 receptor by eledoisin, neurokinin A or neurokinin B were antagonized by both cyclo(GlnTrpPhe(R)-Gly[ANC-2]LeuMet) and cyclo (GlnTrpPheGlyLeuMet) in a manner consistent with the presence in this tissue of a uniform population of receptors, indistinguishable from the NK2 receptor of the rat vas deferens. 4. The compounds cyclo(GlnTrpPheGlyLeuMet) and the lactam-containing analogue are among the most selective antagonists for the NK2 receptor that have been described; their availability should be of value in the characterization of the receptors mediating responses to tachykinins, and in elucidating the physiological functions of the tachykinin receptors.
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PMID:Pharmacological specificity of novel, synthetic, cyclic peptides as antagonists at tachykinin receptors. 166 32


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