In vitro binding and CNS effects of novel neurotensin agonists that cross the blood–brain barrier

Tyler, Beth M.; Douglas, Christopher L.; Fauq, Abdul H.; Pang, Yuan Ping; Stewart, Jennifer A.; Cusack, Bernadette; McCormick, Daniel J.; Richelson, Elliott

doi:10.1016/s0028-3908(99)00011-8

Cited by 69 publications

(56 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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 311supporting

confidence: 78%

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

Pettibone

Hess²,

Hey³

et al. 2002

J Pharmacol Exp Ther

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: Ntr1 Knockout Mice 311supporting

confidence: 78%

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

Pettibone

Hess²,

Hey³

et al. 2002

J Pharmacol Exp Ther

122

View full text Add to dashboard Cite

show abstract

“…Likewise, PD149163, a reduced-amide NT [8][9][10][11][12][13] , showed improved metabolic stability after systemic administration and maintained the analgesic activities of the native NT peptide (65)(66)(67). Subsequently, several additional systemically infused but centrally acting analogs (i.e., NT66L, NT69L, NT79, and ABS212) were synthesized by combining N-terminal modifications and incorporation of non-natural amino acids at positions 8, 9, 11, and 12 (63,64,(68)(69)(70)(71). Finally, in compound JMV2012, the unmodified NT 8-13 fragment has been dimerized and cyclized (72).…”

Section: Figurementioning

confidence: 99%

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

Demeule¹,

Beaudet²,

Régina³

et al. 2014

J. Clin. Invest.

101

View full text Add to dashboard Cite

Neurotensin (NT) has emerged as an important modulator of nociceptive transmission and exerts its biological effects through interactions with 2 distinct GPCRs, NTS1 and NTS2. NT provides strong analgesia when administered directly into the brain; however, the blood-brain barrier (BBB) is a major obstacle for effective delivery of potential analgesics to the brain. To overcome this challenge, we synthesized chemical conjugates that are transported across the BBB via receptor-mediated transcytosis using the brain-penetrant peptide Angiopep-2 (An2), which targets LDL receptor-related protein-1 (LRP1). Using in situ brain perfusion in mice, we found that the compound ANG2002, a conjugate of An2 and NT, was transported at least 10 times more efficiently across the BBB than native NT. In vitro, ANG2002 bound NTS1 and NTS2 receptors and maintained NT-associated biological activity. In rats, i.v. ANG2002 induced a dose-dependent analgesia in the formalin model of persistent pain. At a dose of 0.05 mg/kg, ANG2002 effectively reversed pain behaviors induced by the development of neuropathic and bone cancer pain in animal models. The analgesic properties of ANG2002 demonstrated in this study suggest that this compound is effective for clinical management of persistent and chronic pain and establish the benefits of this technology for the development of neurotherapeutics.

show abstract

“…To overcome the challenge inherent in developing centrally active peptides that retain activity when given systemically, many neurotensin analogs have been generated. One series of compounds using L-neoTrp (Fauq et al, 1998) has proven valuable due to both pharmacokinetic stability and blood-brain barrier penetration capability (Tyler et al, 1999;Tyler-McMahon et al, 2000b;Katz et al, 2001;Remaury et al, 2002). To understand further the antinociceptive actions of these compounds, we have now examined the activity of a series of these analogs in mice both systemically and topically.…”

Section: Introductionmentioning

confidence: 99%

Systemically and Topically Active Antinociceptive Neurotensin Compounds

Rossi¹,

Matulonis²,

Richelson³

et al. 2010

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Neurotensin is a neurotransmitter/modulator with a wide range of actions. Using a series of 10 stable analogs, we have examined neurotensin antinociception in mice. By incorporating (2S)-2-amino-3-(1H-4-indoyl)propanoic acid (L-neoTrp), a series of neurotensin analogs have been synthesized that are stable in serum and are systemically active in vivo. When administered in mice, they all were antinociceptive in the radiant heat tail-flick assay. Time-action curves revealed a peak effect at 30 min and a duration of action ranging from 2 to 4 h. Dose-response curves revealed that two compounds were partial agonists with maximal responses below 75%, whereas all of the remaining compounds displayed a full response. Overall, the compounds were quite potent, with ED 50 values similar to those of opioids. At peak effect, the ED 50 values ranged from 0.91 to 9.7 mg/kg s.c. Two of the analogs were active topically. Together, these studies support the potential of neurotensin analogs as analgesics. They are active systemically and by using them topically, it may be possible to avoid problematic side effects, such as hypothermia and hypotension.

show abstract

In vitro binding and CNS effects of novel neurotensin agonists that cross the blood–brain barrier

Cited by 69 publications

References 29 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

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

Systemically and Topically Active Antinociceptive Neurotensin Compounds

Contact Info

Product

Resources

About