Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have discovered a novel cyclopeptide substance P (SP) antagonist, FK 224 (N-[N2-[N-[N-[N-[2,3-didehydro-N-methyl-N-[N-[3-(2-pentylphenyl )- propionyl]-L-threonyl]tyrosyl-L-leucynyl]-D-phenylalanyl]-L-allo- threonyl]-L-asparaginyl]-L-serine-nu-lactone), which inhibited [3H]SP binding to guinea pig lung membranes in a dose-dependent manner. According to Rosenthal analysis, the inhibitory effect of FK 224 on [3H]SP binding appears to be competitive. In order to clarify the receptor subtype selectivity of FK 224, we have studied the interaction of FK 224 with three tachykinin receptors (NK1, NK2 and NK3) by using receptor binding techniques and in vitro bioassays, and have also compared FK 224 with the novel nonpeptide antagonist, (+/-)-CP-96,345. In binding experiments, FK 224 dose-dependently inhibited [3H]SP binding to rat cerebral cortical membranes (NK1) and [3H]neurokinin (NK) A (NKA) binding to rat duodenum smooth muscle membranes (NK2), but did not affect [3H]eledoisin binding to rat cerebral cortical membranes (NK3). In bioassay experiments, FK 224 inhibited SP-induced contraction of guinea pig ileum (NK1) and NKA-induced contraction of rat vas deferens (NK2) in a dose-dependent manner, but did not affect NKB-induced contraction of rat portal vein (NK3). In contrast, (+/-)-CP-96,345 inhibited SP-induced contraction of guinea pig ileum, but not NKA-induced contraction of rat vas deferens or NKB-induced contraction of rat portal vein. In the presence of FK 224, SP dose-response curves and NKA dose-response curves were shifted to the right in parallel with no depression of the maximal contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:FK 224, a novel cyclopeptide substance P antagonist with NK1 and NK2 receptor selectivity. 137 96

CP-96,345 has been identified as being a highly selective, nonpeptidic agent with subnanomolar affinity for the NK1 receptor. In the present study, we observed that pre but not posttreatment with this agent will produce depression in the second, but not the first phase of the agitation behavior induced by the injection of formalin into a rat's hindpaw. This effect is monotonically dose dependent after intrathecal (10-200 micrograms/10 microliters) or systemic (1-15 mg/kg, ip) administration. Even at the highest dose examined (400 micrograms/10 microliters), there was only a transient motor weakness of the hindpaw. The stereoisomer CP-96,344 has no binding affinity, and has no effect on the formalin response, but shows the same dose profile for motor dysfunction at the highest dose. In contrast, Spantide, a peptidic sP ligand, had only a modest effect upon the formalin response at 1 microgram/10 microliters and produced a prominent, long-lasting motor dysfunction at 4 micrograms/10 microliters. These results provide the first suggestion of sP antagonists having prominent analgesic activity with a significant therapeutic index (analgesic to motor), and emphasizes the probable role of the NK1 class of receptors in the spinal cord in mediating at least one class of nociceptive afferent input.
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PMID:Stereospecific effects of a nonpeptidic NK1 selective antagonist, CP-96,345: antinociception in the absence of motor dysfunction. 172 Nov 2

1. The aim of this study was the pharmacological characterization of tachykinin NK1 and NK2 receptors mediating contraction in the circular muscle of the guinea-pig ileum and proximal colon. The action of substance P (SP), neurokinin A (NKA) and of the synthetic agonists [Sar9]SP sulphone, [Glp6,Pro9]SP(6-11) (septide) and [beta Ala8]NKA(4-10) was investigated. The affinities of various peptide and nonpeptide antagonists for the NK1 and NK2 receptor was estimated by use of receptor selective agonists. 2. The natural agonists, SP and NKA, produced concentration-dependent contraction in both preparations. EC50 values were 100 pM and 5 nM for SP, 1.2 nM and 19 nM for NKA in the ileum and colon, respectively. The action of SP and NKA was not significantly modified by peptidase inhibitors (bestatin, captopril and thiorphan, 1 microM each). 3. Synthetic NK1 and NK2 receptor agonists produced concentration-dependent contraction of the circular muscle of the ileum and proximal colon. EC50 values were 83 pM, 36 pM and 10 nM in the ileum, 8 nM, 0.7 nM and 12 nM in the colon for [Sar9]SP sulphone, septide and [beta Ala8]NKA-(4-10), respectively. The pseudopeptide derivative of NKA(4-10), MDL 28,564 behaved as a full or near-to-full agonist in both preparations, its EC50s being 474 nM and 55 nM in the ileum and colon, respectively. 4. Nifedipine (1 microM) abolished the response to septide and [Sar9]SP sulphone in the ileum and produced a rightward shift and large depression of the response in the colon. The response to [beta Ala8]NKA(4-10) was abolished in the ileum and largely unaffected in the colon. 5. The NK1 receptor antagonists, (+/-)-CP 96,34, FK 888 and GR 82,334 competitively antagonized the response to septide and [Sar9]SP sulphone in both preparations without affecting that to [beta Ala8]NKA(4-10). In general, the NK1 receptor antagonists were significantly more potent toward septide than [Sar9]SP sulphone in both preparations. 6. The NK2 receptor antagonists, GR 94,800 and SR 48,968 selectively antagonized the response to [beta Ala8]NKA(4-10) without affecting that to [Sar9]SP sulphone or septide in the ileum and colon. SR 48,968 produced noncompetitive antagonism of the response to the NK2 receptor agonist in the ileum and competitive antagonism in the colon. 7. MEN 10,376 and the cyclic pseudopeptide MEN 10,573 antagonized in a competitive manner the response to [beta Ala8]NKA(4-10) in the ileum and colon. While MEN 10,573 was equipotent in both preparations, MEN 10,376 was significantly more potent in the colon than in the ileum. MEN 10,376was also effective against septide in both preparations, without affecting the response to [Sar9] SP sulphone. MEN 10,573 antagonized the response to [Sar9]SP sulphone and septide in both preparations,pKB values against septide being intermediate, and significantly different from, those measured against[Beta Ala 8]NKA(4-10) and [Sa9]lSP sulphone.8. These findings show that tachykinin NK1 and NK2 receptors mediate contraction of the circular muscle of the guinea-pig ileum and colon. In both preparations NK1 receptor antagonists display higher apparent affinity when tested against septide than [Sar9]SP sulphone. These findings are compatible with the proposed existence of NK1 receptor subtypes in guinea-pig, although alternative explanations (e.g.agonist binding to different epitopes of the same receptor protein) cannot be excluded at present.Furthermore, an intraspecies heterogeneity of the NK2 receptor in the circular muscle of the guinea-pig ileum and colon is suggested.
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PMID:Comparison of tachykinin NK1 and NK2 receptors in the circular muscle of the guinea-pig ileum and proximal colon. 751 2

The existence of a septide-sensitive subtype of the tachykinin NK1 receptor has been recently proposed. In the rat isolated urinary bladder, the non-peptide NK1 receptor antagonist RP 67,580 exhibits a higher affinity towards septide (pKB 7.57) than towards [Sar9]substance P sulfone (pKB 7.00). In this study we have investigated the pharmacological profile of the non-mammalian tachykinin physalaemin, of the synthetic NK1 receptor agonist GR 73,632 (delta-aminovaleryl[LPro9,NMeLeu10]substance P(7-11)) and of [Glu(OBzl)11]substance P in relation to the putative existence of a septide-sensitive receptor. The activity of [Glu(OBzl)11]substance P at the NK1, NK2 and NK3 receptor was assayed in the guinea-pig ileum NK1 receptor assay (EC50 26 nM), in the rabbit pulmonary artery NK2 receptor assay (weak agonist activity) and in the rat portal vein NK3 receptor assays (no appreciable activity up to 1 microM). GR 73,632, [Glu(OBzl)11]substance P and physalaemin, all produced concentration-dependent contractions of the rat isolated urinary bladder, with EC50 values of 17, 79, and 9 nM, respectively. The responses to the three agonists were very slightly or not modified by the NK2 receptor antagonist SR 48,968 (1 microM). RP 67,580 (0.3-3 microM) produced a concentration-dependent rightward shift of the curve to GR 73,632, [Glu(OBzl)11]substance P and physalaemin without producing depression of their maximal response. Schild plot analysis indicated the competitive nature of the antagonism. The affinity (pKB) of RP 67,580 towards physalaemin, GR 73,632 and [Glu(OBzl)11]substance P was 7.12, 7.56 and 7.95, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:GR 73,632 and [Glu(OBzl)11]substance P are selective agonists for the septide-sensitive tachykinin NK1 receptor in the rat urinary bladder. 753 5

1. Whole cell patch clamp recordings of voltage- and tetrodotoxin-sensitive Na+ currents were made from cultured rat neocortical neurones (E18). The effects of the non-peptide NK1 receptor antagonist, (+/-)-CP-96,345 on Na+ currents was examined, relative to the effect of the local anaesthetic lignocaine and tetrodotoxin. 2. Sodium currents were reversibly depressed by bath application of (+/-)-CP-96,345 with a half-maximally effective concentration of 18 +/- 2 microM at a stimulation frequency of 0.1 Hz. Likewise the concentrations required to half-maximally inhibit sodium currents by tetrodotoxin and lignocaine were 10 +/- 2 nM and 1.3 +/- 0.2 mM respectively. 3. The depression of sodium currents by (+/-)-CP-96,345 (10 microM) was use-dependent in that raising the stimulus frequency from 0.1 Hz to 10 Hz further decreased the magnitude of sodium currents from 60 +/- 5% to 37 +/- 5% of control values respectively. Similarly, the depression of sodium currents by lignocaine (500 microM) and tetrodotoxin (30 nM) was also accentuated by raising the stimulus frequency from 0.1 Hz to 10 Hz. 4. The effect of (+/-)-CP-96,345 was not associated with a change in either the activation or steady-state inactivation characteristics of these currents, suggesting that its mechanism of action was via open channel blockade. 5. These data demonstrate that in addition to antagonizing NK1 receptors, (+/-)-CP-96,345 also acts as a channel blocker on sodium channels at micromolar concentrations, an effect which should be taken into consideration when examining the antinociceptive or anti-inflammatory action of this compound.
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PMID:Block of voltage-dependent sodium currents by the substance P receptor antagonist (+/-)-CP-96,345 in neurones cultured from rat cortex. 840 45

1. The aim of this study was to characterize the receptors mediating the atropine-resistant neurogenic contraction to 5-hydroxytryptamine (5-HT) in the longitudinal muscle of the guinea-pig proximal colon and to determine the type of tachykinin receptors involved in the contractile response to 5-HT by the use of selective antagonists. 2. In the presence of atropine (0.3 microM), guanethidine (5 microM), hexamethonium (100 microM), ketanserin (0.1 microM) and indomethacin (3 microM), 5-HT (0.01-3 microM) produced concentration-dependent neurogenic contractions of colonic strips and at 0.3 microM produced a maximal effect (pEC50 = 7.39 +/- 0.09, n = 18). The 5-HT4 receptor stimulant, 5-methoxytryptamine (5-MeOT, 0.03-10 microM) also produced neurogenic contractions with similar maximum effect to those of 5-HT (pEC50 = 6.89 +/- 0.16). 3. The 5-HT4 receptor antagonist, DAU 6285 (3 microM) shifted the concentration-response curves to both 5-HT and 5-MeOT to the right without significant depression of the maximum, but the 5-HT1/5-HT2 receptor antagonist, metitepine (0.1 microM) and the 5-HT3 receptor antagonist, ondansetron (0.3 microM) had no effect on the control curves to 5-HT and 5-MeOT. 4. The selective NK1 receptor antagonist, FK 888 (1 microM) markedly attenuated the contractions to 5-HT and 5-MeOT. In contrast, the selective NK2 receptor antagonist, SR 48968 (10 nM) and the selective NK3 receptor antagonist, SR 142801 (10 nM) had no effect on the contractions to 5-HT and 5-MeOT. 5. These results indicate that the 5-HT-induced atropine-resistant neurogenic contraction of guinea-pig proximal colon is due to activation of 5-HT4 receptors, presumably located on excitatory motor neurones, innervating the longitudinal muscle. The contraction evoked by activation of the 5-HT4 receptors is mediated primarily via NK1 receptors but not NK2 or NK3, suggesting that the 5-HT4 receptor-mediated contraction is evoked indirectly via tachykinin release from tachykinin-releasing excitatory neurones.
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PMID:Investigation into the 5-hydroxytryptamine-induced atropine-resistant neurogenic contraction of guinea-pig proximal colon. 873 67

1. The aim of this study was to assess the role of tachykinins, acting via NK1 and NK2 receptors, in mediating nonadrenergic noncholinergic (NANC) contractions produced by electrical field stimulation (EFS) in the circular muscle of the rat small intestine. 2. In the presence of atropine (1 microM), guanethidine (3 microM), indomethacin (10 microM), apamin (0.3 microM) and L-nitroarginine (L-NOARG, 100 microM) and after in vitro capsaicin (10 microM for 15 min) pretreatment, EFS (0.25 ms pulse width, 100 V, 1-30 Hz for 5 s) produced a frequency-dependent NANC contraction of mucosa-free circular muscle strips from the rat proximal duodenum and terminal ileum. In the duodenum, the NANC contraction was preceded by a transient NANC relaxation. All responses to EFS were abolished by 1 microM tetrodotoxin. 3. The NK1 receptor selective antagonist, SR 140,333 (0.1 microM for 60 min) and the NK2 receptor selective antagonist, MEN 10,627 (0.1 microM for 60 min), both produced a partial inhibition of the contractile response to EFS. The co-administration of SR 140,333 and MEN 10,627 produced a profound inhibition of the response to EFS in the duodenum, larger than that produced by each antagonist alone; a fraction (about 25% of the response at 30 Hz) of the NANC contraction of the duodenum persisted in the presence of the two antagonists. This residual response was however abolished after co-administration of the NK1 and NK2 receptor antagonists, GR 94,800 (1 microM) and GR 82,334 (10 microM). The co-administration of SR 140,333 and MEN 10,627 nearly abolished the NANC contraction to EFS in the ileum. 4. Nifedipine (1 microM) induced a profound depression of the NANC contraction to EFS in both duodenal and ileal strips. A fraction of the response to EFS (about 25 and 5-10% of the response at 30 Hz in the duodenum and ileum, respectively) was nifedipine-resistant. SR 140,333 (0.1 microM) had little effect on the nifedipine-resistant response to EFS in the duodenum although it reduced by about 50% the response in the ileum. MEN 10,627 (0.1 microM) produced a partial inhibitory effect of the nifedipine-resistant response in both regions. The co-administration of SR 140,333 and MEN 10,627 nearly abolished the nifedipine-resistant response in the ileum while a small fraction (about 20% of control) of the response persisted in the duodenum.
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PMID:Role of tachykinins as excitatory mediators of NANC contraction in the circular muscle of rat small intestine. 874 74

The effect of capsaicin-induced stimulation of afferent neurons on peristalsis and the possible neural mediators involved in this action were examined in the guinea-pig isolated ileum. The intraluminal pressure threshold for eliciting peristaltic waves was used to quantify facilitation (decrease in threshold) or inhibition (increase in threshold) of peristalsis. Capsaicin (0.1-1 microM) caused an initial short-lasting stimulation of peristalsis followed by a prolonged inhibition of peristaltic activity. Capsaicin (1 microM) was ineffective when the gut segments had been pretreated with 3.3 microM capsaicin, which is indicative of an afferent neuron-dependent action of the drug. In contrast, the abolition of peristalsis caused by a high concentration of capsaicin (33 microM) was fully reversible on removal and reproducible on readministration of capsaicin, a feature characteristic of a nonspecific depression of smooth muscle excitability. Baseline peristalsis and the excitatory/inhibitory effect of capsaicin (1 microM) on peristalsis remained unaltered by a combination of the tachykinin NK1 receptor antagonist (+)-(2S, 3S)-3-(2-methoxybenzylamino)-2-phenyl piperidine (CP-99,994; 0.3 microM) and the tachykinin NK2 receptor antagonist (L(-)-N-methyl-N[4-acetylamino-4-phenyl-piperidine-2-(3,4- -dichlorophenyl)butyl]-benzamide (SR-48,968; 0.1 microM). Further experiments, performed in the presence of a low concentration of atropine (10 nM) showed that the calcitonin gene-related peptide (CGRP) antagonist human alpha-calcitonin gene-related peptide (8-37) [hCGRP(8-37); 10 microM] attenuated the delayed inhibitory effect of capsaicin on peristalsis, but did not influence baseline peristaltic activity and the capsaicin-induced facilitation of peristalsis. Blockade of nitric oxide (NO) synthesis by NG-nitro-L-arginine methylester (L-NAME, 300 microM) facilitated baseline peristaltic activity and reduced the delayed inhibition of peristalsis caused by capsaicin (1 microM) without affecting the initial peristalsis-stimulating action of capsaicin. The effects of L-NAME were prevented by L-arginine (1 mM). The data of the current study indicate that capsaicin-sensitive afferent neurons do not participate in the neural pathways subserving peristalsis in the guinea-pig small intestine, but modulate peristaltic activity upon stimulation with capsaicin. The initial stimulant action of capsaicin on peristalsis is independent of tachykinins acting via NK1 or NK2 receptors, while the delayed capsaicin-induced depression of peristalsis involves CGRP and NO.
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PMID:The inhibitory modulation of guinea-pig intestinal peristalsis caused by capsaicin involves calcitonin gene-related peptide and nitric oxide. 875 Sep 23

We have determined the ability of the novel nonpeptide tachykinin (TK) NK3 receptor antagonist, SR 142801, [(S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl)-N-methylaceta mide] in inhibiting the nitric oxide (NO)-independent prejunctional inhibition of cholinergic twitches and the NO-dependent relaxation produced by the NK3 receptor selective agonist, senktide, in the circular muscle of the guinea-pig proximal colon. Under moderate load (10 mN) and isometric recording of mechanical activity, single pulse electrical field stimulation (EFS) produced atropine- and tetrodotoxin-sensitive twitch contractions of mucosa-free circular muscle strips from the guinea-pig proximal colon. In the presence of NK1 and NK2 receptor antagonists (SR 140333 0.01 microM and GR 94800 0.1 microM, respectively) the NK3 receptor selective agonist, senktide (EC50 33 pM) and the NK3 receptor preferring natural TK, neurokinin B (NKB, EC50 13 pM) produced a concentration-dependent slowly developing inhibition of cholinergic twitches. Senktide (1 nM) did not affect the contractile response to acetylcholine (1 microM) indicating that depression of evoked twitches occurs prejunctionally. The inhibitory effect of senktide was unaffected when evoked in the presence of the cyclooxygenase inhibitor (S)-ketoprofen (10 microM), guanethidine (10 microM), naloxone (0.3 microM), the GABAB receptor antagonist 2-hydroxysaclofen (10 microM) or the combined application of the adenosine A1 and A2 receptor antagonists, 8-cyclopentyl-1,3-dipropylxanthine (10 microM) and 3,7-dimethyl-1-propargylxanthine (30 microM) respectively. In the presence of NK1 and NK2 receptor antagonists, the NO-synthase inhibitor L-nitroarginine (L-NOARG 30-100 microM) did not affect twitch inhibition induced by senktide (EC50 33 pM). The response to NKB (EC50 95 pM) was slightly reduced by L-NOARG, yet the bulk of the inhibitory effect of both agonists on cholinergic twitches was substantially independent of NO generation. SR 142801 (0.1-0.3 microM) produced a moderate rightward shift of the concentration-response curve to senktide without depression of the Emax to the agonist, yielding an apparent pKB value of 7.65. Under low resting tone (3 mN) and isotonic recording of mechanical activity, mucosa-free circular muscle strips from the guinea-pig proximal colon gained a high intrinsic tone suitable for testing the response to relaxant agents. In the presence of atropine (1 microM), guanethidine (3 microM), SR 140333 (0.01 microM) and GR 94800 (0.1 microM), senktide (EC50 50 pM) produced a concentration-dependent relaxation of the strips, which was blocked by L-NOARG. SR 142801 (0.01-0.1 microM) produced a large rightward shift of the L-NOARG-sensitive concentration-response curve to senktide yielding an apparent pKB value of 8.62. Under isometric recording condition, SR 142801 (0.1 microM) did not affect twitch inhibition produced by 3 nM clonidine. Under isotonic recording condition, SR 142801 did not affect the L-NOARG-sensitive relaxation produced by EFS. The present results indicate that NK3 receptor stimulation produces a NO-dependent relaxation of the guinea-pig colon and a substantially NO-independent prejunctional inhibition of cholinergic twitches. The variable affinities of SR 142801 in antagonizing various senktide-induced neuromodulatory effects in the guinea-pig intestine suggest a possible intraspecies heterogeneity of NK3 receptors in the enteric nervous system.
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PMID:Effect of SR 142801 on nitric oxide-dependent and independent responses to tachykinin NK3 receptor agonists in isolated guinea-pig colon. 875 Oct 80

Tachykinins belong to an evolutionarily conserved family of peptide neurotransmitters. The mammalian tachykinins include substance P, neurokinin A and neurokinin B, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated NK1, NK2 and NK3, respectively. Tachykinin receptors have been cloned and contain seven segments spanning the cell membrane, indicating their inclusion in the G-protein-linked receptor family. The continued development of selective agonists and antagonists for each receptor has helped elucidate roles for these mediators, ranging from effects in the central nervous system to the perpetuation of the inflammatory response in the periphery. Various selective ligands have shown both inter- and intraspecies differences in binding potencies, indicating distinct binding sites in the tachykinin receptor. The interaction of tachykinin with its receptor activates Gq, which in turn activates phospholipase C to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on specific receptors in the sarcoplasmic reticulum to release intracellular stores of Ca2+, while DAG acts via protein kinase C to open L-type calcium channels in the plasma membrane. The rise in intracellular [Ca2+] induces the tissue response. With an array of actions as diverse as that seen with tachykinins, there is scope for numerous therapeutic possibilities. With the development of potent, selective non-peptide antagonists, there could be potential benefits in the treatment of a variety of clinical conditions, including chronic pain, Parkinson's disease, Alzheimer's disease, depression, rheumatoid arthritis, irritable bowel syndrome and asthma.
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PMID:Tachykinins: receptor to effector. 892 4


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