Pharmacophore Identification for Sigma-1 (&amp;#963;1) Receptor Binding: Application of the "Deconstruction - Reconstruction - Elaboration" Approach

Ra, Glennon

doi:10.2174/138955705774329519

Cited by 131 publications

(124 citation statements)

References 25 publications

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“…33 The butylene intermediate chain determines the optimal distance between the primary B and secondary A hydrophobic centers proposed by the Glennon's model. [34][35][36] The compound with the highest affinity is the butylene derivative 3a (R = H), with K i (σ 1 ) value of 2.6 nM and an interesting selectivity ratio K i (σ 2 )/K i (σ 1 ) = 46.2. The para-substituted compound 3d (R=4-Cl), instead, still maintains an appreciable σ 1 affinity but has a selectivity ratio (K i (σ 2 )/K i (σ 1 )=5.1) lower than those of the unsubstituted derivatives.…”

Section: Resultsmentioning

confidence: 99%

“…The choice of a propyl or butyl chain is dictated by the fact that both fall within the range of optimal distances between the basic nitrogen atom and hydrophobic primary site in the receptor model of Glennon. [34][35][36] All compounds obtained were subsequently tested in order to assess their affinity and their selectivity toward σ receptors. As mentioned previously, the crystal structure of both σ 1 and σ 2 receptors remains unsolved to date.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, Biological Evaluation, and Three-Dimensional in Silico Pharmacophore Model for σ₁ Receptor Ligands Based on a Series of Substituted Benzo[d]oxazol-2(3H)-one Derivatives

et al. 2009

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Novel benzo [d ]oxazol-2(3H )-one derivatives were designed and synthesized, and their affinities against σ receptors were evaluated. On the basis of 31 compounds, a three-dimensional pharmacophore model for the σ 1 receptor binding site was developed using the Catalyst 4.9 software package. The best 3D pharmacophore hypothesis, consisting of one positive ionizable, one hydrogen bond acceptor, two hydrophobic aromatic, and one hydrophobic features provided a 3D-QSAR model with a correlation coefficient of 0.89. The best hypothesis was also validated by three independent methods, i.e., the Fisher randomization test included in the CatScramble functionality of Catalyst, the leave-one-out test, and activity prediction of an additional test set. The achieved results will allow researchers to use this 3D pharmacophore model for the design and synthesis of a second generation of high affinity σ 1 ligands, as well as to discover other lead compounds for this class of receptors.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis, Biological Evaluation, and Three-Dimensional in Silico Pharmacophore Model for σ₁ Receptor Ligands Based on a Series of Substituted Benzo[d]oxazol-2(3H)-one Derivatives

et al. 2009

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“…The remarkable history of the S1R extends from the late 1970s and early 1980s (Martin et al, 1976;Su, 1981Su, , 1988Tam, 1983;Vaupel, 1983;Tam and Cook, 1984;Largent et al, 1986Largent et al, , 1987Sircar et al, 1986a;Weber et al, 1986;Itzhak, 1987;McLean and Weber, 1988;Sharkey et al, 1988;Bowen et al, 1989;de Costa et al, 1989;Hellewell and Bowen, 1990) to the present day. The reader is directed to the earlier publications and reviews that outline the original pharmacologic identification of this important receptor (Martin, 1983;Su and Hayashi, 2003;Glennon, 2005).…”

Section: Introductionmentioning

confidence: 99%

Biochemical Pharmacology of the Sigma-1 Receptor

2015

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The sigma-1 receptor (S1R) is a 223 amino acid two transmembrane (TM) pass protein. It is a non-ATP-binding nonglycosylated ligand-regulated molecular chaperone of unknown three-dimensional structure. The S1R is resident to eukaryotic mitochondrial-associated endoplasmic reticulum and plasma membranes with broad functions that regulate cellular calcium homeostasis and reduce oxidative stress. Several multitasking functions of the S1R are underwritten by chaperone-mediated direct (and indirect) interactions with ion channels, G-protein coupled receptors and cell-signaling molecules involved in the regulation of cell growth. The S1R is a promising drug target for the treatment of several neurodegenerative diseases related to cellular stress. In vitro and in vivo functional and molecular characteristics of the S1R and its interactions with endogenous and synthetic small molecules have been discovered by the use of pharmacologic, biochemical, biophysical, and molecular biology approaches. The S1R exists in monomer, dimer, tetramer, hexamer/octamer, and higher oligomeric forms that may be important determinants in defining the pharmacology and mechanism(s) of action of the S1R. A canonical GXXXG in putative TM2 is important for S1R oligomerization. The ligand-binding regions of S1R have been identified and include portions of TM2 and the TM proximal regions of the C terminus. Some client protein chaperone functions and interactions with the cochaperone 78-kDa glucose-regulated protein (binding immunoglobulin protein) involve the C terminus. Based on its biochemical features and mechanisms of chaperone action the possibility that the S1R is a member of the small heat shock protein family is discussed.

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“…Additionally, the C and aromatic moiety (Ph) from the pharmacophore are located in areas of bulky hydrophobic tolerance. 25 This presence of two hydrophobic pockets may accommodate several binding modes for a single compound. 25,26 From the current study, it can be extrapolated that the polycyclic cage may prove useful in future studies to delineate binding to these two hydrophobic pockets, and therefore binding modes, as compared to the use of only aromatic rings as seen in many of the compounds published.…”

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confidence: 99%

3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (σ1) receptor

Geldenhuys

Novotny

Malan

et al. 2013

Bioorganic & Medicinal Chemistry Letters

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Pentacycloundecylamine (PCU) derived compounds have been shown to be promising lead structures for the development of novel drug candidates aimed at a variety of neurodegenerative and psychiatric diseases. Here we show for the first time a 3D quantitative structure-activity relationship (3D-QSAR) for a series of aza-PCU-derived compounds with activity at the sigma-1 (r1) receptor. A comparative molecular field analysis (CoMFA) model was developed with a partial least squares cross validated (q 2 ) regression value of 0.6, and a non-cross validated r 2 of 0.9. The CoMFA model was effective at predicting the sigma-1 activities of a test set with an r 2 >0.7. We also describe here the docking of the PCU-derived compounds into a homology model of the sigma-1 (r1) receptor, which was developed to gain insight into binding of these cage compounds to the receptor.Based on docking studies we evaluated in a [ 3 H]pentazocine binding assay an oxa-PCU, NGP1-01 (IC50 = 1.78 lM) and its phenethyl derivative (IC50 = 1.54 lM). Results from these studies can be used to develop new compounds with specific affinity for the sigma-1(r1) Sigma receptors were initially thought to belong to the opiate receptor family, but were later shown to better associate with another unique family of small proteins. 1 These receptors are now divided into two subtypes denoted as sigma-1 (r 1 ) and sigma-2 (r 2 ). 2,3 These relatively small receptors act as chaperone molecules where, upon agonist activation, they are able to translocate from the endoplasmic reticulum (ER) to the cell membrane. 4 The two main sigma receptors were found to differ in size, the sigma-1 receptor being a rv29 kDa single polypeptide 5 and the sigma-2 receptor ranging in size between 18 and 21.5 kDa. 6 Additionally, the sigma-1 receptor has been cloned, whereas the sigma-2 receptor has not been cloned to date. 5,6 The sigma receptor signaling pathway still remains to be fully elucidated but current literature suggests that the sigma receptor protein plays a role in cellular stress by modulation of calcium flux in the ER as well as mitochondria. 7,4,8,9 Recently, it has been shown in

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Pharmacophore Identification for Sigma-1 (σ1) Receptor Binding: Application of the "Deconstruction - Reconstruction - Elaboration" Approach

Cited by 131 publications

References 25 publications

Synthesis, Biological Evaluation, and Three-Dimensional in Silico Pharmacophore Model for σ₁ Receptor Ligands Based on a Series of Substituted Benzo[d]oxazol-2(3H)-one Derivatives

Synthesis, Biological Evaluation, and Three-Dimensional in Silico Pharmacophore Model for σ₁ Receptor Ligands Based on a Series of Substituted Benzo[d]oxazol-2(3H)-one Derivatives

Biochemical Pharmacology of the Sigma-1 Receptor

3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (σ1) receptor

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Pharmacophore Identification for Sigma-1 (&#963;1) Receptor Binding: Application of the "Deconstruction - Reconstruction - Elaboration" Approach

Cited by 131 publications

References 25 publications

Synthesis, Biological Evaluation, and Three-Dimensional in Silico Pharmacophore Model for σ1 Receptor Ligands Based on a Series of Substituted Benzo[d]oxazol-2(3H)-one Derivatives

Synthesis, Biological Evaluation, and Three-Dimensional in Silico Pharmacophore Model for σ1 Receptor Ligands Based on a Series of Substituted Benzo[d]oxazol-2(3H)-one Derivatives

Biochemical Pharmacology of the Sigma-1 Receptor

3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (σ1) receptor

Contact Info

Product

Resources

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Pharmacophore Identification for Sigma-1 (σ1) Receptor Binding: Application of the "Deconstruction - Reconstruction - Elaboration" Approach

Synthesis, Biological Evaluation, and Three-Dimensional in Silico Pharmacophore Model for σ₁ Receptor Ligands Based on a Series of Substituted Benzo[d]oxazol-2(3H)-one Derivatives

Synthesis, Biological Evaluation, and Three-Dimensional in Silico Pharmacophore Model for σ₁ Receptor Ligands Based on a Series of Substituted Benzo[d]oxazol-2(3H)-one Derivatives