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

A series of 14 mutants on nine selected residues of the human tachykinin NK(2) receptor was produced and stably transfected into CHO cells to investigate the binding of the peptide MEN 11420 and the nonpeptide SR 48968 antagonists. The main interactions found for MEN 11420 were with Thr171, Tyr206, Tyr266 and Phe270. In the case of SR 48968 crucial residues were Tyr266 and Tyr289. While some overlapping of the binding sites exists, the binding modes suggested by this study appear not to allow structural correlation, and therefore general SAR, between these two antagonists.
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PMID:Molecular determinants of peptide and nonpeptide NK-2 receptor antagonists binding sites of the human tachykinin NK-2 receptor by site-directed mutagenesis. 1081 58

1. The effects of substance P (SP), acting at NK1 receptors, on the excitability and inspiratory activity of hypoglossal (XII) motoneurons (MNs) were investigated using rhythmically active medullary-slice preparations from neonatal mice (postnatal day 0-3). 2. Local application of the NK1 agonist [SAR(9),Met (O(2))(11)]-SP (SP(NK1)) produced a dose-dependent, spantide- (a non-specific NK receptor antagonist) and GR82334-(an NK1 antagonist) sensitive increase in inspiratory burst amplitude recorded from XII nerves. 3. Under current clamp, SP(NK1) significantly depolarized XII MNs, potentiated repetitive firing responses to injected currents and produced a leftward shift in the firing frequency-current relationships without affecting slope. 4. Under voltage clamp, SP(NK1) evoked an inward current and increased input resistance, but had no effect on inspiratory synaptic currents. SP(NK1) currents persisted in the presence of TTX, were GR82334 sensitive, were reduced with hyperpolarization and reversed near the expected E(K). 5. Effects of the alpha(1)-noradrenergic receptor agonist phenylephrine (PE) on repetitive firing behaviour were virtually identical to those of SP(NK1). Moreover, SP(NK1) currents were completely occluded by PE, suggesting that common intracellular pathways mediate the actions of NK1 and alpha(1)-noradrenergic receptors. In spite of the similar actions of SP(NK1) and PE on XII MN responses to somally injected current, alpha(1)-noradrenergic receptor activation potentiated inspiratory synaptic currents and was more than twice as effective in potentiating XII nerve inspiratory burst amplitude. 6. GR82334 reduced XII nerve inspiratory burst amplitude and generated a small outward current in XII MNs. These observations, together with the first immunohistochemical evidence in the newborn for SP immunopositive terminals in the vicinity of SP(NK1)-sensitive inspiratory XII MNs, support the endogenous modulation of XII MN excitability by SP. 7. In contrast to phrenic MNs (Ptak et al. 2000), blocking NMDA receptors with AP5 had no effect on the modulation of XII nerve activity by SP(NK1). 8. In conclusion, SP(NK1) modulates XII motoneuron responses to inspiratory drive primarily through inhibition of a resting, postsynaptic K+ leak conductance. The results establish the functional significance of SP in controlling upper airway tone during early postnatal life and indicate differential modulation of motoneurons controlling airway and pump muscles by SP.
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PMID:Modulation of hypoglossal motoneuron excitability by NK1 receptor activation in neonatal mice in vitro. 1145 63

N-[(R,R)-(E)-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (DNK333, 1b) has been reported to be a potent and balanced dual neurokinin (tachykinin) receptor antagonist. A recent clinical trial using DNK333 has shown that it blocks the NKA-induced bronchoconstriction in patients with asthma. A series of six analogues 3-8 derived from modification of 3,5-bis(trifluoromethyl)benzamide moiety of DNK333 has been synthesized to serve as the dual NK(1)/NK(2) receptor probes. The 3,5-dinitro substituted benzamide compound 3 was found to possess potent and balanced dual NK(1)/NK(2) receptor antagonist activities (pK(b)=8.4 for the NK(1) receptors, pK(b)=7.87 for the NK(2) receptors) in the functional assay using guinea pig trachea. Furthermore, SAR analysis suggests that steric, electronic, and lipophilic characteristics of substituents in the benzamide region of DNK333 have a crucial effect on both the NK(1) and NK(2) receptor antagonist activities.
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PMID:Design and synthesis of 3,5-disubstituted benzamide analogues of DNK333 as dual NK1/NK2 receptor probes. 1716 59

Ultrasound vocalizations (USVs) known as 22kHz are usual components of the defensive responses of rats exposed to threatening conditions. The amount of emission of 22kHz USVs depends on the intensity of the aversive stimuli. While moderate fear causes an anxiolytic-sensitive enhancement of the defensive responses, high fear tended to reduce the defensive performance of the animals to aversive stimuli. The dorsal periaqueductal gray (dPAG) is an important vocal center and a crucial structure for the expression of defensive responses. Substance P (SP) is involved in the modulation of the defensive response at this midbrain level, but the type of neurokinin receptors involved in this action is not completely understood. In this study we examined whether local injections of the selective NK-1 agonist SAR-MET-SP (10-100 pmol/0.2microL) into the dPAG (i) cause anxiogenic effects in the elevated plus-maze (EPM) (Exp. I), (ii) influence the novelty-induced 22kHz USVs recorded within the frequency range of 20-26kHz (Exp. II) and (iii) change the nociceptive reactivity to heat applied to the rat's tail (Exp III). The data obtained showed that SAR-MET-SP elicited significant "anxiety-like" behaviors, as revealed by the decrease in the number of entries into and time spent onto the open arms of the EPM. These anxiogenic effects were accompanied with antinociception and disruption of the novelty-induced increase in the number and duration of 22kHz USVs. These findings are in agreement with the notion that NK-1 receptors of the dPAG may be an important neurochemical target for new selective drugs aimed at the control of pathological anxiety states.
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PMID:Anxiogenic effects of activation of NK-1 receptors of the dorsal periaqueductal gray as assessed by the elevated plus-maze, ultrasound vocalizations and tail-flick tests. 1798 25