Synthesis and σ receptor affinity of regioisomeric spirocyclic furopyridines

Miyata, Kengo; Schepmann, Dirk; Wünsch, Bernhard

doi:10.1016/j.ejmech.2014.06.073

Cited by 72 publications

(63 citation statements)

References 42 publications

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“…Membrane preparation from guinea pig brains (σ 1 receptor) and rat liver (σ 2 receptor) were employed as receptor material. [ 3 H]‐(+)‐Pentazocine and [ 3 H]di‐ o ‐tolylguanidine served as radioactive competitors in the σ 1 and σ 2 assay, respectively …”

Section: Resultsmentioning

confidence: 99%

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Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ₁ receptor affinity

Fanter

Schepmann

Wünsch

2017

Archiv der Pharmazie

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The aim of this work was to transfer the established chiral-pool synthesis of 1,2, 4-trisubstituted 1,4-diazepanes in solution on the solid phase. For this purpose, (S)-configured amino acids, (S)-alanine, and (S)-leucine, with a small methyl and a larger isobutyl moiety were attached to the solid support 9 by reductive amination. After five reaction steps on the solid support, the 1,4-diazepanes (S)-19a,b were cleaved off and reductively alkylated to afford the 1,2,4-trisubstituted 1,4-diazepanes (S)-20a and (S)-21b, respectively. Both compounds show high σ 1 affinity and selectivity over the σ 2 subtype. K E Y W O R D S1,2,4-trisubstituted 1,4-diazepanes, σ 1 receptor ligands, chiral-pool synthesis, solid-phase organic synthesis, subtype selectivity

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Section: Resultsmentioning

confidence: 99%

“…The affinity of the synthesized 1,4‐diazepanes toward σ 1 and σ 2 receptors was recorded as described in refs . The affinity toward the PCP binding site of the NMDA receptor was recorded as reported in refs …”

Section: Methodsmentioning

confidence: 99%

Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ₁ receptor affinity

Fanter

Schepmann

Wünsch

2017

Archiv der Pharmazie

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“…[29][30][31] Up to a test compound concentration of 10 lM the diastereomeric propellanamines syn-3 and anti-3 did not interact with r 1 and r 2 receptors.…”

Section: Biological Activitymentioning

confidence: 95%

Stereoselective synthesis and pharmacological evaluation of [4.3.3]propellan-8-amines as analogs of adamantanamines

Torres‐Gómez

Lehmkuhl

Frehland

et al. 2015

Bioorganic & Medicinal Chemistry

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“…[55][56][57] Relationshipsbetween structure and s 1 affinity were evaluated using assay data. Reagents and conditions:a)Pd(OAc) 2 (10 mol %), 1,10-phenanthroline (10 mol %), LiBF 4 (1.5 equiv), TEMPO (0.5 equiv), DMAc, 100 8C, 48 h(see Ta ble 1f or yields);b)[Pd(dppf)Cl 2 ]·CH 2 Cl 2 (5 mol %), PPh 3 (10 mol %), Ag 2 CO 3 (2 equiv),H 2 O, 115 8C, microwave irradiation,9 0min;c )[Pd(dppf)Cl 2 ]·CH 2 Cl 2 (5 mol %), PPh 3 (10 mol %), Ag 2 CO 3 (2 equiv), H 2 O, 60 8C, oil bathh eating, 24 h( see Ta ble 1f or yields).…”

Section: S Receptor Affinitymentioning

confidence: 99%

Thiazole‐Based σ₁ Receptor Ligands: Diversity by Late‐Stage C−H Arylation of Thiazoles, Structure–Affinity and Selectivity Relationships, and Molecular Interactions

et al. 2017

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Spirocyclic thiophene derivatives represent promising σ ligands with high σ affinity and selectivity over the σ subtype. To increase ligand efficiency, the thiophene ring was replaced bioisosterically by a thiazole ring, and the pyran ring was opened. Late-stage diversification by regioselective C-H arylation of thiazoles 9 a-c resulted in a set of 53 compounds with high diversity. This set of compounds was analyzed with respect to σ affinity, σ /σ selectivity, lipophilicity (logD ), lipophilicity-corrected ligand efficiency (LELP), and molecular target interactions. The most promising candidates were pyridyl-substituted thiazole derivatives 33 c (2-(1-benzyl-4-ethoxypiperidin-4-yl)-5-(pyridin-3-yl)thiazole) and 34 c (2-(1-benzyl-4-ethoxypiperidin-4-yl)-5-(pyridin-4-yl)thiazole), possessing low-nanomolar σ affinity (K =1.3 and 1.9 nm), high σ /σ selectivity (>1500-fold), low lipophilicity (logD =1.8) and very good ligand efficiency (LELP=5.5), indicating promising pharmacodynamics and pharmacokinetics. Molecular simulation studies, including docking and deconvolution of the free binding energy into its major components, led to decreased hydrophobic stabilization of pyridyl derivatives 33 c and 34 c, which was compensated by lower desolvation energy.

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Synthesis and σ receptor affinity of regioisomeric spirocyclic furopyridines

Cited by 72 publications

References 42 publications

Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ₁ receptor affinity

Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ₁ receptor affinity

Stereoselective synthesis and pharmacological evaluation of [4.3.3]propellan-8-amines as analogs of adamantanamines

Thiazole‐Based σ₁ Receptor Ligands: Diversity by Late‐Stage C−H Arylation of Thiazoles, Structure–Affinity and Selectivity Relationships, and Molecular Interactions

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Synthesis and σ receptor affinity of regioisomeric spirocyclic furopyridines

Cited by 72 publications

References 42 publications

Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ1 receptor affinity

Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ1 receptor affinity

Stereoselective synthesis and pharmacological evaluation of [4.3.3]propellan-8-amines as analogs of adamantanamines

Thiazole‐Based σ1 Receptor Ligands: Diversity by Late‐Stage C−H Arylation of Thiazoles, Structure–Affinity and Selectivity Relationships, and Molecular Interactions

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Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ₁ receptor affinity

Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ₁ receptor affinity

Thiazole‐Based σ₁ Receptor Ligands: Diversity by Late‐Stage C−H Arylation of Thiazoles, Structure–Affinity and Selectivity Relationships, and Molecular Interactions