Disease relevance of Septide

• SPOME (100-300 nM) inhibited peristalsis by a rise of the pressure threshold at which peristaltic waves were triggered, whereas septide and GR-73 632 (30-300 nM) interrupted peristalsis by causing circular muscle spasms [1].
• Binding experiments performed with [(125)I]-NKA allowed us to demonstrate the presence of "septide-sensitive" specific binding sites on membranes from rat CHO cells transfected with the NK(1) receptor cDNA (CHO-rat-NK1 cells), human astrocytoma U373 MG, or mouse cortical astrocytes, cells which express NK(1) but neither NK(2) nor NK(3) receptors [2].
• The selectivity of this compound for the latter receptor was confirmed by its failure to affect SP- or septide-induced hypotension in either guinea pigs or rats [3].
• Intravenous administration of the undecapeptide [Sar9]substance P (SP) sulfone (1.5 nmol/kg) and the hexapeptide [Glp6,Pro9]SP(6-11) (septide; 0.4 nmol/kg) produced a comparable (about 30-40% of maximal effect) increase of insufflation pressure (bronchospasm) in anesthetized guinea-pigs [4].
• These findings confirm that tachykinins mediate edema formation via the NK(1) receptor and provide direct evidence that the septide-sensitive binding site is on the NK(1) receptor [5].

High impact information on Septide

• The 'septide-sensitive' tachykinin receptor: still an enigma [6].
• Septide (SEP; a highly selective substance P analog), neurokinin A (NKA), and neurokinin B (NKB) elicited endogenous ACh release in a concentration-dependent manner [7].
• Smaller doses of the antagonists inhibited the effects of SEP compared to NKA, and the effects of NKB could only be antagonized by SPA [7].
• Septide-like peptides, including septide and NKA, were potent competitors (in the nanomolar range) of [3H]ALIE-124 specific binding site [8].
• High affinity binding of [3H]propionyl-[Met(O2)11]substance P(7-11), a tritiated septide-like peptide, in Chinese hamster ovary cells expressing human neurokinin-1 receptors and in rat submandibular glands [8].

Biological context of Septide

• However, ALIE-124 stimulated phosphatidylinositol hydrolysis, as previously shown for septide-like peptides [8].
• SR 140333 blocked the stimulatory effect of this agonist (10(-7) M) with an IC50 of 1.6 x 10(-9) M, whereas the effect of another NK1 agonist, septide (EC50 = 1.5 x 10(-8) M) was antagonized with an IC50 of 2.1 x 10(-10) M [9].
• Dose-response curves showed that septide was a more potent bronchoconstrictor than [Sar(9),Met(O(2))(11)]SP to cause bronchoconstriction [10].
• 4. All antagonists except LY303241 blocked dose-dependently the increases in vascular permeability to equipotent doses of [Sar9, Met(O2)11]SP and septide [11].
• 4. The NK1r antagonists, CP-99994 (2S,3S)-3-(2-methoxybenzyl)amino-2-phenylpiperidine dihydrochloride and MEN-10581, cyclo(Leu,[CH2NH]Lys(benzyloxycarbonyl)-Gln-Trp-Phe-betaAla) were both more potent in inhibiting endocytosis (50 x and 8 x greater respectively) against septide than against SP [12].

Anatomical context of Septide

• The hexapeptide [pGlu6,Pro9]substance P (SP)6-11, septide, has been shown to be an agonist as potent as SP in eliciting smooth muscle contraction in several in vitro preparations, while being a poor competitor of labeled SP binding [13].
• Septide was a weak competitor of [3H]SP binding, with dissociation constants (Ki) of 2.9 +/- 0.6 microM and 3.7 +/- 0.9 microM for membranes and intact transfected cells, respectively [13].
• Our data indicate that in rat parotid gland, the existence of a specific "septide-sensitive" receptor can be ruled out and that only the NK1 receptor is present and mediates cellular responses [14].
• 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 [15].
• 3. In a number of spinal cord neurones (n = 17) only septide induced a membrane depolarization while DiMe-C7 elicited no response [16].

Associations of Septide with other chemical compounds

• RP67580 is apparently as potent at antagonizing septide, SP, or SP(4-11) (in all cases KB = 3 nM) [14].
• Increasing the dose of RP 67,580 3 fold resulted in inhibition of the response to SP (0.2 nmol) and [Sar9]SP sulphone (0.002 nmol) by approximately 66% and 64% respectively with the response to septide being inhibited by approximately 70%.(ABSTRACT TRUNCATED AT 250 WORDS)[17]
• In contrast, (D-Arg1, D-Pro2,4, D-Phe7, D-His9)-SP (0.5-1.0 nmol) and (D-Phe7, D-His9)-SP (6-11) (0.5-2.0 nmol) inhibited only SP-induced behavioral response, but not physalaemin- or septide-induced response [18].
• The tachykinin NK1 and NK3 receptor agonists septide and senktide, respectively, were ineffective [19].
• The analog [pGlu6,Pro9] SP(6-11) (septide) may also act on atypical NK-1 receptors in guinea pig ileum [20].

Gene context of Septide

• 2. The synthetic tachykinin receptor agonists, septide (pD2 7.87) and [Sar9]substance P (SP) sulphone (pD2 7.64) produced concentration-dependent contractions of the rat isolated urinary bladder [21].
• 1. The NK1 tachykinin receptor agonists, septide, [Sar9,Met(O2)11]SP and [Pro9]SP produced locomotor hyperactivity (10-20 min) when injected intracerebroventricularly (i.c.v.) in the guinea-pig [22].
• When administered simultaneously with NK-1 receptor agonists, a putative SP antagonist, spantide inhibited SP-, physalaemin- and septide-induced behavioral response in a dose-dependent manner with ED50 values of 1.0, 0.65 and 1.3 nmol/mouse, respectively [18].
• 1. Following the recent proposal that the selective agonist septide, ([pGlu6,Pro9]SP(6-11)), acts on a novel tachykinin receptor distinct from the 'classical' NK1 receptor, the aim of the study was to investigate the possible heterogeneity of tachykinin NK1 receptors in the rat urinary bladder [21].
• Septide, an agonist with a low affinity for NK-1 binding sites, [Sar9, Met(O2)11]SP and to a lesser extent [Pro9]SP, two potent and selective NK-1 agonists were the most effective drugs in stimulating these behaviours [23].

Analytical, diagnostic and therapeutic context of Septide

• Therefore, following the blockade of tachykinin NK1, NK2 and septide-sensitive receptors, the accumulation of inositol monophosphate appears to be a valuable, rapid and sensitive bioassay for determining the activity of NK3 receptor agonists and putative NK3 receptor antagonists [24].

References