Functional activity of new C-terminal cyclic-neurotensin fragment analogs

Akunne, Hyacinth C.; Darling, S; Zoski, Kim; Sefler, Andrea M.; He, John X.; Sawyer, Tomi K.; Pugsley, Thomas A.; Cody, Wayne L.

doi:10.1016/s0143-4179(96)90066-9

Cited by 8 publications

(9 citation statements)

References 6 publications

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“…One cyclic compound, NaMeArg 8 -cyclo[Cys-Pro-Trp-Pen]-Leu 13 (Pen ¼ penicillamine) was found to have nanomolar affinity towards NTS 1 , but exhibited antagonistic activity. 107,108 A cyclic dimer of NT was generated JMV2012, c(KKPYILKKPYIL), and showed in vivo antinociceptive potency in the abdominal constriction model, in a dose-dependent manner, with statistically significant analgesia extending out to 1 h after iv injection when compared to saline. 109 NT can incorporate bulky modifications on the N-terminus, and a polyamine-NT analog was synthesized.…”

Section: Nt-based Agonists With Antinociceptive Activitiesmentioning

confidence: 99%

Anticonvulsant neuropeptides as drug leads for neurological diseases

Robertson¹,

Flynn²,

White³

et al. 2011

Nat. Prod. Rep.

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Anticonvulsant neuropeptides are best known for their ability to suppress seizures and modulate pain pathways. Galanin, neuropeptide Y, somatostatin, neurotensin, dynorphin, among others, have been validated as potential first-in-class anti-epileptic or/and analgesic compounds in animal models of epilepsy and pain, but their therapeutic potential extends to other neurological indications, including neurodegenerative and psychatric disorders. Disease-modifying properties of neuropeptides make them even more attractive templates for developing new-generation neurotherapeutics. Arguably, efforts to transform this class of neuropeptides into drugs have been limited compared to those for other bioactive peptides. Key challenges in developing neuropeptide-based anticonvulsants are: to engineer optimal receptor-subtype selectivity, to improve metabolic stability and to enhance their bioavailability, including penetration across the blood–brain barrier (BBB). Here, we summarize advances toward developing systemically active and CNS-penetrant neuropeptide analogs. Two main objectives of this review are: (1) to provide an overview of structural and pharmacological properties for selected anticonvulsant neuropeptides and their analogs and (2) to encourage broader efforts to convert these endogenous natural products into drug leads for pain, epilepsy and other neurological diseases.

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Section: Nt-based Agonists With Antinociceptive Activitiesmentioning

confidence: 99%

Anticonvulsant neuropeptides as drug leads for neurological diseases

Robertson¹,

Flynn²,

White³

et al. 2011

Nat. Prod. Rep.

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“…Compared to linear peptides, macrocyclic compounds have emerged as an important class of therapeutics by combining favorable properties, such as enhanced conformational rigidity, improved pharmacokinetic properties, and increased target selectivity and binding affinity. − Peptide cyclization has shown great success toward generating active NT analogs targeting NTS1 (Figure ). Indeed, head-to-tail ( M1 and M2 ), head-to-side-chain ( M3 , M4 , and M5 ), and side-chain-to-side-chain ( M6 and M7 ) peptide cyclization of NT(8-13) have all provided macrocyclic analogs with relatively high affinities for NTS1, ranging from 16 nM to 3.5 μM. − Of particular note, most of these cyclic analogs of NT(8-13) were found to behave as NTS1 agonists using in vitro functional assays (except M7 , which seems to act as an antagonist) . Furthermore, M2 and its dimeric counterpart M8 showing similar binding affinity for both NTS1 and NTS2 (150 nM) were further found to exhibit in vivo biological activity, inducing hypothermic and analgesic effects following systemic administration. , Recently, we searched for optimized macrocyclization sites on NT(8-13) and found that macrocycles formed via ring-closing metathesis (RCM) between the side chains of alkene-functionalized amino acid in position 8 and the ortho allylated tyrosine residue in position 11 of NT(8-13) ( M9 - M12 ) showed greatly improved plasma stability, high binding affinity toward both NTS1 and NTS2, and potent analgesic action in vivo (Figure ).…”

Section: Introductionmentioning

confidence: 99%

“…Macrocyclic NT(8-13) analogs previously described in the literature. Data taken from ref ( M1 , M3 , M6 , and M7 ); ref ( M2 ); ref ( M4 ); ref ( M5 ); ref ( M8 ); ref ( M9 ), and ref ( M10 , M11 , and M12 ). K i ’s for NTS1 are values reported in the original articles.…”

Section: Introductionmentioning

confidence: 99%

Design, Structural Optimization, and Characterization of the First Selective Macrocyclic Neurotensin Receptor Type 2 Non-opioid Analgesic

et al. 2021

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Neurotensin (NT) receptor type 2 (NTS2) represents an attractive target for the development of new NT-based analgesics. Here, we report the synthesis and functional in vivo characterization of the first constrained NTS2-selective macrocyclic NT analog. While most chemical optimization studies rely on the NT(8-13) fragment, we focused on NT(7-12) as a scaffold to design NTS2-selective macrocyclic peptides. Replacement of Ile 12 by Leu, and Pro 7 /Pro 10 by allylglycine residues followed by cyclization via ring-closing metathesis led to macrocycle 4, which exhibits good affinity for NTS2 (50 nM), high selectivity over NTS1 (>100 μM), and improved stability compared to . In vivo profiling in rats reveals that macrocycle 4 produces potent analgesia in three distinct rodent pain models, without causing the undesired effects associated with NTS1 activation. We further provide evidence of its nonopioid antinociceptive activity, therefore highlighting the strong therapeutic potential of NTS2-selective analogs for the management of acute and chronic pain.

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“…To date, only a handful of studies have been reported on the implementation of macrocyclization on NT. 21,22 Interestingly, head-to-tail cyclization of NT (8−13) resulted in analogues that display central physiological effects when injected intravenously. 23,24 At the outset of this study aimed at identifying suitable sites for macrocyclization on NT, there was evidence that several peptidergic GPCRs recognized turn structures.…”

mentioning

confidence: 99%

“…In addition to increased proteolytic stability, macrocyclization allows control over peptide conformations and fine-tuning of their structural properties, in addition to providing insights on the receptor’s tolerance to ligand conformational changes. To date, only a handful of studies have been reported on the implementation of macrocyclization on NT. , Interestingly, head-to-tail cyclization of NT (8–13) resulted in analogues that display central physiological effects when injected intravenously. , …”

mentioning

confidence: 99%

In Search of the Optimal Macrocyclization Site for Neurotensin

Sousbie

Besserer-Offroy

Brouillette

et al. 2018

ACS Med. Chem. Lett.

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Neurotensin exerts potent analgesic effects following activation of its cognate GPCRs. In this study, we describe a systematic exploration, using structure-based design, of conformationally constraining neurotensin (8-13) with the help of macrocyclization and the resulting impacts on binding affinity, signaling, and proteolytic stability. This exploratory study led to a macrocyclic scaffold with submicromolar binding affinity, agonist activity, and greatly improved plasma stability.

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Functional activity of new C-terminal cyclic-neurotensin fragment analogs

Cited by 8 publications

References 6 publications

Anticonvulsant neuropeptides as drug leads for neurological diseases

Anticonvulsant neuropeptides as drug leads for neurological diseases

Design, Structural Optimization, and Characterization of the First Selective Macrocyclic Neurotensin Receptor Type 2 Non-opioid Analgesic

In Search of the Optimal Macrocyclization Site for Neurotensin

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