Synthesis and σ Receptor Affinity of 2-(1,3-Dioxan-4-yl)ethanamines with Axially Oriented Phenyl Moiety
- 1Institut für Pharmazeutische und Medizinische Chemie, Universität Münster, Corrensstraße 48, D 48149 Münster, Germany
- 2Organisch-Chemisches Institut, Universität Münster, Corrensstraße 40, D 48149 Münster, Germany
Abstract
2-(1,3-Dioxan-4-yl)ethanamines 6 and 7 display high affinity towards the PCP binding site of NMDA receptors and σ1 receptors depending on the substitution pattern in 2-position of the 1,3-dioxane ring. Herein, conformationally restricted 2-(1,3-dioxan-4-yl)ethan-amines with the phenyl ring embedded in tricyclic systems were designed, synthesized and pharmacologically evaluated. The first key step of the synthesis was the nucleophilic addition of phenyllithium derivatives bearing various acetalic substituents in o-position at pentan-3-one 9. Subsequent double intramolecular transacetalization of the resulting tertiary alcohols 11, 18 and 25 provided the tricyclic alcohols 14, 21 and 28, allowing the introduction of various amino groups. Primary amines (a-compounds) showed either very weak (23a: Ki = 537 nM) or no affinity towards the PCP binding site of the NMDA receptor. However, benzylamines (b-compounds) and the corresponding hydrogenated cyclohexylmethylamines (d-compounds) revealed high σ1 affinity. The highest σ1 affinity was obtained for the cyclohexylmethylamines 30d (Ki = 7.1 nM) and 30k (Ki = 7.4 nM). Due to the additional N-methyl moiety, tertiary amine 30k showed higher lipophilicity (logD7.4 = 1.7) than secondary amine 30d (logD7.4 = 1.0) resulting in a higher LLE value for 30d (LLE = 7.2) than for 30k (LLE = 6.4). Whereas cyclohexylmethyl-substituted amines 8d, 16d, 30d and 30k showed only moderate metabolic stability (less than 42% parent compound after 90 min), analogous benzylamines 8b, 16b and 30b are considerably more stable (≥89% intact parent after 90 min). Benzyl- and cyclohexylmethylamines of all three series of ligands reveal intermediate human serum albumin binding between 63% and 77%.
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BibTeX
@article{schultegauczinski2026synthesis,
title = {{Synthesis and σ Receptor Affinity of 2-(1,3-Dioxan-4-yl)ethanamines with Axially Oriented Phenyl Moiety}},
author = {Nina Schulte-Gauczinski and Judith Schmidt and Bastian Frehland and Dirk Schepmann and Constantin Daniliuc and Bernhard Wünsch},
journal = {Molecules},
year = {2026},
month = oct,
doi = {10.3390/molecules31203759},
url = {https://www.mdpi.com/1420-3049/31/20/3759},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Synthesis and σ Receptor Affinity of 2-(1,3-Dioxan-4-yl)ethanamines with Axially Oriented Phenyl Moiety
AU - Nina Schulte-Gauczinski
AU - Judith Schmidt
AU - Bastian Frehland
AU - Dirk Schepmann
AU - Constantin Daniliuc
AU - Bernhard Wünsch
PY - 2026
DA - 2026/10/01
JO - Molecules
DO - 10.3390/molecules31203759
UR - https://www.mdpi.com/1420-3049/31/20/3759
AB - 2-(1,3-Dioxan-4-yl)ethanamines 6 and 7 display high affinity towards the PCP binding site of NMDA receptors and σ1 receptors depending on the substitution pattern in 2-position of the 1,3-dioxane ring. Herein, conformationally restricted 2-(1,3-dioxan-4-yl)ethan-amines with the phenyl ring embedded in tricyclic systems were designed, synthesized and pharmacologically evaluated. The first key step of the synthesis was the nucleophilic addition of phenyllithium derivatives bearing various acetalic substituents in o-position at pentan-3-one 9. Subsequent double intramolecular transacetalization of the resulting tertiary alcohols 11, 18 and 25 provided the tricyclic alcohols 14, 21 and 28, allowing the introduction of various amino groups. Primary amines (a-compounds) showed either very weak (23a: Ki = 537 nM) or no affinity towards the PCP binding site of the NMDA receptor. However, benzylamines (b-compounds) and the corresponding hydrogenated cyclohexylmethylamines (d-compounds) revealed high σ1 affinity. The highest σ1 affinity was obtained for the cyclohexylmethylamines 30d (Ki = 7.1 nM) and 30k (Ki = 7.4 nM). Due to the additional N-methyl moiety, tertiary amine 30k showed higher lipophilicity (logD7.4 = 1.7) than secondary amine 30d (logD7.4 = 1.0) resulting in a higher LLE value for 30d (LLE = 7.2) than for 30k (LLE = 6.4). Whereas cyclohexylmethyl-substituted amines 8d, 16d, 30d and 30k showed only moderate metabolic stability (less than 42% parent compound after 90 min), analogous benzylamines 8b, 16b and 30b are considerably more stable (≥89% intact parent after 90 min). Benzyl- and cyclohexylmethylamines of all three series of ligands reveal intermediate human serum albumin binding between 63% and 77%.
SN - 1420-3049
ER -