Rational design of novel neurotensin mimetics: Discovery of a pharmacologically unprecedented agent exhibiting concentration-dependent dual effects as antagonist and full agonist

Pang, Yuan Ping; Zaidi, J. H.; Kozikowski, Alan P.; Cusack, Bernadette; Richelson, Elliott

doi:10.1007/bf00125377

Cited by 5 publications

(3 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We previously reported the development of two partial nonpeptidic neurotensin (8 -13), abbreviated as NT(8 -13), 1 mimetics whose Arg 8 -Arg 9 -Pro 10 portion is replaced with substituted indole-2-carboxylates as the partially flexible non-peptidic equivalents by our multiple template approach (1)(2)(3). NT (8 -13) is a peptide fragment of neurotensin (NT) and is more biologically relevant than the parent peptide (4).…”

mentioning

confidence: 99%

Proposed Ligand Binding Site of the Transmembrane Receptor for Neurotensin(8–13)

Pang

Cusack

Groshan

et al. 1996

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Recently, we reported the development of a species-specific neurotensin analog that displays selective binding affinity at the rat and human neurotensin (NT) receptor, L-[3,2'-Nal11]NT(8-13) (where Nal is naphthylalanine) (NT19). We have developed another neurotensin analog, L-[3,1'-Nal11]NT(8-13), (NT34), that exhibits a 126-fold difference in binding affinities between the rat and human receptors. This compound differs from our previous reported species-specific ligand in the steric positioning of the naphthyl ring on the L-alanine side chain. For NT34, the observed Kd values at the rat and human neurotensin receptors were 0.046 and 5.8 nM, respectively. In stimulating phosphatidylinositol turnover, the observed EC50 values were 2.8 nM and 130 nM in rat and human, respectively. We constructed a series of chimeric rat/human neurotensin receptor genes and expressed them by transient transfection into human embryonic kidney (HEK-293) cells. Radioligand binding assays were then performed using neurotensin and NT34. Our results led us to propose a region of the neurotensin receptor that may be involved in determining species specificity, i. e. the transmembrane VI, the third extracellular loop, and transmembrane VII regions of the neurotensin receptor.

show abstract

mentioning

confidence: 99%

Proposed Ligand Binding Site of the Transmembrane Receptor for Neurotensin(8–13)

Pang

Cusack

Groshan

et al. 1996

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Among these were a series of NT(8−10)-substituted compounds containing indole-2-carboxylates with guanidine appendages. These had micromolar binding affinities for the NT receptors − . An alkylation at the 3-position of the indole was initially reported and later reassigned .…”

Section: Identifying the Active Fragment Of Ntmentioning

confidence: 99%

Cancer, Chemistry, and the Cell: Molecules that Interact with the Neurotensin Receptors

et al. 2009

View full text Add to dashboard Cite

The literature covering neurotensin (NT) and its signalling pathways, receptors, and biological profile is complicated by the fact that the discovery of three NT receptor subtypes has come to light only in recent years. Moreover, a lot of this literature explores NT in the context of the central nervous system and behavioral studies. However, there is now good evidence that the up-regulation of NT is intimately involved in cancer development and progression. This Review aims to summarize the isolation, cloning, localization, and binding properties of the accepted receptor subtypes (NTR1, NTR2, and NTR3) and the molecules known to bind at these receptors. The growing role these targets are playing in cancer research is also discussed. We hope this Review will provide a useful overview and a one-stop resource for new researchers engaged in this field at the chemistry-biology interface.

show abstract

“…There is evidence that neurotensin 8 -13 fragment is biologically active in the conformation of b-rotation. Indeed, replacement of the Pro 10 -Tyr 11 fragment by a b-rotation mimetic preserves the ability of binding to neurotensin receptors [12,13]. Then, it was natural to suggest that the neuroleptic activity of derivatives of the Pro 10 -Tyr 11 dipeptide can be further increased by using additional interactions realized in the neurotensin 8 -13 fragment.…”

Section: Design Of the Neurotensinergic Dipeptide Neuroleptic Drug DImentioning

confidence: 99%

Design of the Neurotensinergic Dipeptide Neuroleptic Drug Dilept

Gudasheva

Зайцева

2005

Pharm Chem J

View full text Add to dashboard Cite

An approach to the design of dipeptide neuroleptics free of extrapyramidal effects is described. Proceeding from an original hypothesis about the peptidergic mechanism of action of the atypical neuroleptic drug sulpiride and using the method of drug-based peptide synthesis, a peptide prototype of sulpiride -Pro-Tyr-NH 2 dipeptide -was obtained whose neuroleptic activity and the absence of cataleptogenic properties were revealed by tests on experimental animals. An analysis of the structures of known neuropeptides showed that the Pro-Tyr dipeptide sequence coincides with a Pro 10 -Tyr 11 fragment of the tridecapeptide neurotensin referred to in the literature as a neuropeptide with neuroleptic properties. Further design based on the obtained active dipeptide structure and the supposed bioactive b-rotational conformation of the neurotensin 8 -13 sequence led to a group of new potential atypical neuroleptics, N-acylprolyltyrosines. The structure of these tripeptoid analogs of neurotensin contains an N-acyl group imitating the Leu 13 side chain of neurotensin, which plays an important role in receptor binding. One of these compounds, N-caproyl-Lprolyl-L-tyrosine methyl ester, was named Dilept and chosen for more extensive pharmacological characterization as a potential antipsychotic agent. Preclinical investigations showed that Dilept is effective in doses 0.4 -4.0 mg/kg (i.p.) and retains activity upon peroral administration. The drug is nontoxic and does not induce extrapyramidal disorders even when administered in amounts 1000 times higher than the effective dose. 230 0091-150X/05/3905-0230

show abstract

Rational design of novel neurotensin mimetics: Discovery of a pharmacologically unprecedented agent exhibiting concentration-dependent dual effects as antagonist and full agonist

Cited by 5 publications

References 33 publications

Proposed Ligand Binding Site of the Transmembrane Receptor for Neurotensin(8–13)

Proposed Ligand Binding Site of the Transmembrane Receptor for Neurotensin(8–13)

Cancer, Chemistry, and the Cell: Molecules that Interact with the Neurotensin Receptors

Design of the Neurotensinergic Dipeptide Neuroleptic Drug Dilept

Contact Info

Product

Resources

About