Pharmacokinetics of Novel Hexapeptides with Neurotensin Activity in Rats.

Machida, Ryouichi; Tokumura, Tadakazu; Tsuchiya, Yutaka; Sasaki, Atsushi; Abe, Kouichi

doi:10.1248/bpb.16.43

Cited by 33 publications

(15 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most, if not all, of these CNS effects of NT can be mimicked by systemic dosing of metabolically stable analogs of NT, most notably NT-2 (Machida et al, 1993;Sarhan et al, 1997) and NT69L (Cusack et al, 2000;Tyler-McMahon et al, 2000). NT is also known for its pharmacological effects on certain peripheral functions, including effects on intestinal motor and secretory activity (Kitabgi and Freychet, 1978), as well as certain ef- fects on endocrine and neuroendocrine function (Brown and Miller, 1982).…”

Section: Discussionmentioning

confidence: 99%

“…Like i.c.v. NT, the peripheral administration of the metabolically stable, brain-penetrant NT analog NT-2 (Machida et al, 1993;Banks et al, 1995) to wild-type mice also caused hypothermia, hot-plate analgesia, and reduced rotarod performance in vivo, but again these effects were absent in the NTR1 knockout mice. These results substantiate the importance of NTR1 in these activities and confirm the utility of these brain-penetrant NT analogs in studying the CNS actions of NT (Pugsley et al, 1995;Sarhan et al, 1997;Tyler et al, 1999;Cusack et al, 2000;Tyler-McMahon et al, 2000).…”

Section: Ntr1 Knockout Mice 311mentioning

confidence: 99%

See 1 more Smart Citation

The Effects of Deleting the Mouse Neurotensin Receptor NTR1 on Central and Peripheral Responses to Neurotensin

Pettibone

Hess²,

Hey³

et al. 2002

The Journal of Pharmacology and Experimental Therapeutics

122

View full text Add to dashboard Cite

Mice deficient in the neurotensin (NT)-1 receptor (NTR1) were developed to characterize the NT receptor subtypes that mediate various in vivo responses to NT. F2 generation (C57BL6/ Sv129J) NTR1 knockout (Ϫ/Ϫ) mice were viable, and showed normal growth and overt behavior. The Ϫ/Ϫ mice lacked detectable NTR1 radioligand binding in brain, whereas NTR2 receptor binding density appeared normal compared with wildtype (ϩ/ϩ) mice. The gene deletion also resulted in the loss of NTR1 expression as determined by reverse transcription-polymerase chain reaction and in situ hybridization. Intracerebroventricular injection of NT (1 g) to ϩ/ϩ mice caused a robust hypothermic response (5-6°C) and a significant increase in hot-plate latency. These effects were absent in the Ϫ/Ϫ mice. Similar results were obtained with i.p. injections of the brainpenetrant NT analog NMe-Arg-Lys-Pro-Trp-Tle-Leu (NT-2, 1 mg/kg i.p.). NT-2 administration also impaired rotarod performance in wild-type mice, but had no effect on motor coordination in knockout mice. In vitro, NT and NT-2 at 30 nM caused predominantly contraction and relaxation in isolated distal colon and proximal ileum, respectively, from ϩ/ϩ mice, but no responses were observed with tissues from Ϫ/Ϫ mice. A similar loss of the contractile effects of NT was observed in the isolated stomach fundus from the knockout mice. In vivo, NT-2 administration reduced colonic propulsion substantially in wild-type mice. In contrast, NT-2 had no effect in NTR1 null mice, whereas the hypomotility effect of clonidine was intact. These data indicate that NTR1 mediates several of the central and peripheral effects of NT.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Ntr1 Knockout Mice 311mentioning

confidence: 99%

The Effects of Deleting the Mouse Neurotensin Receptor NTR1 on Central and Peripheral Responses to Neurotensin

Pettibone

Hess²,

Hey³

et al. 2002

The Journal of Pharmacology and Experimental Therapeutics

122

View full text Add to dashboard Cite

show abstract

“…All culture media were from Invitrogen (Cergy Pontoise, France). NT, neuromedin N, JMV449 (Doulut et al, 1992), and EISAI-2 (Machida et al, 1993) were from Neosystem (Strasbourg, France). EISAI-1 (Machida et al, 1993) was a generous gift of Eisai Co., Ltd. (Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…NT, neuromedin N, JMV449 (Doulut et al, 1992), and EISAI-2 (Machida et al, 1993) were from Neosystem (Strasbourg, France). EISAI-1 (Machida et al, 1993) was a generous gift of Eisai Co., Ltd. (Tokyo, Japan). Primary structures of these agonists are presented in Table 1 Receptor Expression and Cell Cultures.…”

Section: Methodsmentioning

confidence: 99%

Differential Involvement of Intracellular Domains of the Rat NTS1 Neurotensin Receptor in Coupling to G Proteins: A Molecular Basis for Agonist-Directed Trafficking of Receptor Stimulus

Skrzydelski

Lhiaubet²,

Lebeau³

et al. 2003

Molecular Pharmacology

View full text Add to dashboard Cite

In this work, we evidenced characteristic features of agonistinduced trafficking of receptor stimulus for the rat neurotensin receptor 1 (NTS1). Thus, reverse potency orders between two agonists, EISAI-1 and neuromedin N, were observed in inositol 1,4,5-trisphosphate and cAMP assays in Chinese hamster ovary cells transfected with this receptor. Indeed, compared with other agonists, EISAI-1 presented lower relative potency toward inositol 1,4,5-trisphosphate production than toward cAMP accumulation, guanosine 5Ј-O -(3-[35 S]thio)triphosphate binding, and [3 H]arachidonic acid production. These results indicated pathway-dependent differences in EISAI-1 intrinsic efficacies, favoring activations of G s -and G i/o -related pathways over the G q/11 -related pathway. Moreover, although coupling to G q/11 and G i/o involved the third intracellular loop and the C-terminal domain of the NTS1 receptor, respectively, we demonstrated that deletion of the latter domain suppressed agonist-induced cAMP accumulation, suggesting that this domain also mediated coupling to G s . Together, these results indicated that, unlike other agonists, EISAI-1 discriminated between the pathways involving the receptor C-terminal domain and that involving the third intracellular loop. These properties of EISAI-1 were also observed in cortical neurons endogenously expressing the NTS1 receptor. They were further attributed to the functionalization of its COOH end by an ethyl group, because the unesterified analog EISAI-2 presented normal behavior on inositol 1,4,5-trisphosphate production.These findings support the hypothesis of agonist-selective receptor states with distinct conformations or accessibilities of intracellular domains. They also suggest that the differential involvement of these domains in coupling to G proteins might represent a molecular basis for agonist-selective responses through G protein-coupled receptors.It is now well established that a single G protein-coupled receptor (GPCR) can interact with several G proteins or other transducing molecules, thereby activating multiple signaling pathways. Moreover, several studies revealed that a ligand could show differential abilities to trigger these pathways (Kenakin, 1996(Kenakin, , 2001Berg et al., 1998;Brink et al., 2000;Wenzel-Seifert and Seifert, 2000). One important implication of this finding is the possibility of developing drugs acting selectively on one of the responses associated to a receptor.Essentially two mechanisms could lead to agonist-selective activation of effector pathways: differential strength of signaling and agonist-directed trafficking of receptor stimulus (Kenakin, 1995). The first mechanism relies on differential tightness of coupling between the receptor and the various transducing molecules. Agonists of high efficacy will thus induce a pleiotropic response, whereas agonists of low efficacy will trigger only the most efficiently coupled pathway. The second mechanism relies on pathway-dependent differences in agonist intrinsic efficacies. This mec...

show abstract

“…We previously reported that the degradation of (Me)Arg-Lys-Pro-Trp-tertLeu-Leu-OEt (NT-1) and nikkomycin Z, which were hydrolyzed in the solution, were accelerated in rat plasma. [5][6][7][8] We therefore theorized that SPN degradation might also be accelerated in rat plasma. However, the stability of SPN in rat plasma has not been reported, and the blood, serum, and plasma samples in the pharmacokinetic studies were treated without considering the stability of SPN in the samples.…”

mentioning

confidence: 99%

Stability of Spironolactone in Rat Plasma: Strict Temperature Control of Blood and Plasma Samples Is Required in Rat Pharmacokinetic Studies

Tokumura

Muraoka

Masutomi

et al. 2005

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

Spironolactone, 3-(3-oxo-7a-acetylthio-17b-hydroxy-4-androsten-17a-yl)propionic acid g-lactone (SPN), is a competitive aldosterone antagonist, which is used as a potassiumsparing diuretic in premature infants to reduce lung congestion. 1-3)The stability of SPN in solution was reported by Pramar and Gupta. In the study, SPN was most stable at pH 4.5, and the degradation rate increased with increasing and decreasing pH. The apparent first-order rate constant of SPN at 40°C in pH 7.3 buffer solutions was 8.3ϫ10Ϫ4 h Ϫ1. 4) SPN degradation seemed to be a type of hydrolysis. We previously reported that the degradation of (Me)Arg-Lys-Pro-Trp-tertLeu-Leu-OEt (NT-1) and nikkomycin Z, which were hydrolyzed in the solution, were accelerated in rat plasma. [5][6][7][8] We therefore theorized that SPN degradation might also be accelerated in rat plasma. However, the stability of SPN in rat plasma has not been reported, and the blood, serum, and plasma samples in the pharmacokinetic studies were treated without considering the stability of SPN in the samples. If SPN in the samples is unstable, the pharmacokinetic data reported are believed to be incorrect. We therefore began a study into SPN stability in rat plasma.In this report, SPN stability in rat plasma is first described, and then the pharmacokinetic SPN data is shown in rats after an intravenous administration of 20 mg/kg obtained with temperature strictly controlled for plasma and blood samples. MATERIALS AND METHODS Materials Measurement of Stability in Rat PlasmaSPN was dissolved in ethanol to make a 1 mg/ml solution. Male SpragueDawley rat plasma previously prepared and stored at Ϫ80°C was used to measure the kinetics of SPN degradation. The pH value of the rat plasma was 7.8 at the start and the end of each experiment. The concentration of NaF in the plasma was 20 mg/ml. Immediately before each experiment, suitable aliquots of the plasma with or without NaF were pre-incubated for 15 min at 0°C, 23.5°C, and 37°C. The experiments were performed at 0-1°C, 23.5Ϯ0.5°C, and 37Ϯ0.5°C. Those temperatures were employed as the lowest temperature for treatment of plasma samples, usual room temperature, and body temperature, respectively. The experiments were initiated by adding the SPN solution to produce a final concentration of 20 mg/ml. A 200 ml aliquot of methanol containing 0.2% HClO 4 was added to 100 ml of sample solution immediately after it was taken from the reaction mixture, and cooled in an ice-bath. The mixture was stirred in a vortex mixer for 30 s and centrifuged at 3000 rpm for 10 min; 50 ml of the supernatant was injected into the chromatograph.Determination of SPN in Rat Plasma by HPLC The concentration of SPN in plasma was determined with an HPLC assay consisting of a Model LC-9A pump, equipped with a Model SCL-6B system controller, a Model SPD-6A UV spectrophotometric detector, a Model CTO-6A column oven, a Model C-R4AX Chromatopac, and a Model SIL-6B autoinjector, all from Shimadzu (Kyoto, Japan). The mobile phase was acetonitrile-water-perchloric acid ...

show abstract

Pharmacokinetics of Novel Hexapeptides with Neurotensin Activity in Rats.

Cited by 33 publications

References 0 publications

The Effects of Deleting the Mouse Neurotensin Receptor NTR1 on Central and Peripheral Responses to Neurotensin

The Effects of Deleting the Mouse Neurotensin Receptor NTR1 on Central and Peripheral Responses to Neurotensin

Differential Involvement of Intracellular Domains of the Rat NTS1 Neurotensin Receptor in Coupling to G Proteins: A Molecular Basis for Agonist-Directed Trafficking of Receptor Stimulus

Stability of Spironolactone in Rat Plasma: Strict Temperature Control of Blood and Plasma Samples Is Required in Rat Pharmacokinetic Studies

Contact Info

Product

Resources

About