Highly Potent 4-Amino-indolo[2,3-<i>c</i>]azepin-3-one-Containing Somatostatin Mimetics with a Range of sst Receptor Selectivities

Feytens, Debby; Vlaeminck, Magali De; Cescato, Renzo; Tourwé, Dirk; Reubi, Jean Claude

doi:10.1021/jm801205x

Cited by 17 publications

(9 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7,86,87 Unlike most of the literature on SRIF inhibitors that focuses on the β-turn backbone conformation of somatostatin, Tourweá nd co-workers investigated the importance of the side chain orientation of the D-Trp-Lys residues. 88,89 The design of these somatostatin peptidomimetics was based on the constrained Trp residues D-and L-Aia (104−108, Figure 19). Initially, D-Aia was introduced in the linear tetrapeptide 104 that contains the four essential side chains for sst receptor binding to provide compound 105.…”

Section: ■ Somatostatinmentioning

confidence: 99%

“…Analogue 110 on the other hand can be considered a broad spectrum sst ligand that binds to all subtypes in the nanomolar to subnanomolar range. 89 The authors thus concluded that the D-Aia-Lys dipeptide represents a universally recognized sst 1−5 pharmacophore. Despite the fact that the Aia scaffold prefers extended conformations rather than turn conformations, 58 it displays the ability to adopt trans or gauche side chain orientations.…”

Section: ■ Somatostatinmentioning

confidence: 99%

“…137 This example elegantly illustrates the broad applicability of the azepinone scaffold at different receptor targets. Several small peptidomimetics, e.g., for the opioid and somatostatin receptors, have been prepared based on this scaffold 88,89 as well as enzyme inhibitors. 36,40,41 Endogenous opioid peptides such as endomorphin II (Figure 27) have also been used as starting point in search of improved opioid ligands.…”

Section: ■ Opioid Peptidesmentioning

confidence: 99%

“…On the basis of the results outlined above, the d -Aia-Lys dipeptide core was used to prepare a series of somatostatin dipeptide mimetics. , Interestingly, different receptor subtype selectivity profiles were observed depending on whether the N- and C-termini were capped with various moieties ( 109 – 113 ). It was proposed that the introduction of a substituent at the N-terminus targets the receptor pocket occupied by Phe of the native ligand.…”

Section: Somatostatinmentioning

confidence: 99%

See 3 more Smart Citations

Side Chain Cyclized Aromatic Amino Acids: Great Tools as Local Constraints in Peptide and Peptidomimetic Design

et al. 2016

Self Cite

View full text Add to dashboard Cite

Constraining the conformation of flexible peptides is a proven strategy to increase potency, selectivity, and metabolic stability. The focus has mostly been on constraining the backbone dihedral angles; however, the correct orientation of the amino acid side chains (χ-space) that constitute the peptide pharmacophore is equally important. Control of χ-space utilizes conformationally constrained amino acids that favor, disfavor, or exclude the gauche (-), the gauche (+), or the trans conformation. In this review we focus on cyclic aromatic amino acids in which the side chain is connected to the peptide backbone to provide control of χ- and χ-space. The manifold applications for cyclized analogues of the aromatic amino acids Phe, Tyr, Trp, and His within peptide medicinal chemistry are showcased herein with examples of enzyme inhibitors and ligands for G protein-coupled receptors.

show abstract

Section: ■ Somatostatinmentioning

confidence: 99%

Section: ■ Somatostatinmentioning

confidence: 99%

Section: ■ Opioid Peptidesmentioning

confidence: 99%

Section: Somatostatinmentioning

confidence: 99%

See 2 more Smart Citations

Side Chain Cyclized Aromatic Amino Acids: Great Tools as Local Constraints in Peptide and Peptidomimetic Design

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…S5) and two agonists (27) (Fig. S6) to all five candidate structures (InactiveConf1, InactiveConf2, InactiveConf3, ActiveConf1, and ActiveConf2).…”

Section: Ligand Binding Studiesmentioning

confidence: 99%

Conformational and Thermodynamic Landscape of GPCR Activation from Theory and Computation

Dong

Goddard

Abrol

2016

Biophysical Journal

View full text Add to dashboard Cite

We present a hybrid computational methodology to predict multiple energetically accessible conformations for G protein-coupled receptors (GPCRs) that might play a role in binding to ligands and different signaling partners. To our knowledge, this method, termed ActiveGEnSeMBLE, enables the first quantitative energy profile for GPCR activation that is consistent with the qualitative profile deduced from experiments. ActiveGEnSeMBLE starts with a systematic coarse grid sampling of helix tilts/rotations (∼13 trillion transmembrane-domain conformations) and selects the conformational landscape based on energy. This profile identifies multiple potential active-state energy wells, with the TM3-TM6 intracellular distance as an approximate activation coordinate. These energy wells are then sampled locally using a finer grid to find locally minimized conformation in each energy well. We validate this strategy using the inactive and active experimental structures of β2 adrenergic receptor (hβ2AR) and M2 muscarinic acetylcholine receptor. Structures of membrane-embedded hβ2AR along its activation coordinate are subjected to molecular-dynamics simulations for relaxation and interaction energy analysis to generate a quantitative energy landscape for hβ2AR activation. This landscape reveals several metastable states along this coordinate, indicating that for hβ2AR, the agonist alone is not enough to stabilize the active state and that the G protein is necessary, consistent with experimental observations. The method's application to somatostatin receptor SSTR5 (no experimental structure available) shows that to predict an active conformation it is better to start from an inactive structure template based on a close homolog than to start from an active template based on a distant homolog. The energy landscape for hSSTR5 activation is consistent with hβ2AR in the role of the G protein. These results demonstrate the utility of the ActiveGEnSeMBLE method for predicting multiple conformations along the pathways for activating GPCRs and the corresponding energy landscapes, thereby providing detailed structural insights into the initial molecular events of GPCR function that are not easily accessible by experiments.

show abstract

Aspects of Peptidomimetics

Maes¹,

Tourwé²

2009

Peptide and Protein Design for Biopharmaceutical Applications

View full text Add to dashboard Cite

Highly Potent 4-Amino-indolo[2,3-c]azepin-3-one-Containing Somatostatin Mimetics with a Range of sst Receptor Selectivities

Cited by 17 publications

References 53 publications

Side Chain Cyclized Aromatic Amino Acids: Great Tools as Local Constraints in Peptide and Peptidomimetic Design

Side Chain Cyclized Aromatic Amino Acids: Great Tools as Local Constraints in Peptide and Peptidomimetic Design

Conformational and Thermodynamic Landscape of GPCR Activation from Theory and Computation

Aspects of Peptidomimetics

Contact Info

Product

Resources

About