Stereoselective Synthesis and Biological Evaluation of Perhydroquinoxaline-Based κ Receptor Agonists
Abstract
1. Introduction
2. Results and Discussion
2.1. Synthesis
2.2. Biological Evaluation
2.3. Molecular Modeling
2.4. Conclusions
3. Materials and Methods
3.1. Synthetic Procedures
- Diethyl 3-(tert-butyldimethylsilyloxy)glutarate (5)
- 3-(tert-Butyldimethylsilyloxy)pentanedial (6)
- (2r,5s)-N1,N3-Dibenzyl-5-(tert-butyldimethylsilyloxy)-2-nitrocyclohexane-1,3-diamine ((2r,5s)-7a) and
- (2r,5r)-N1,N3-dibenzyl-5-(tert-butyldimethylsilyloxy)-2-nitrocyclohexane-1,3-diamine ((2r,5r)-7b)
- (2r,5s)-N1,N3-Dibenzyl-5-(tert-butyldimethylsilyloxy)-2-nitrocyclohexane-1,3-diamine ((2r,5s)-7a)
- (2r,5s)-N1,N3-Dibenzyl-5-(tert-butyldimethylsilyloxy)cyclohexane-1,2,3-triamine ((2r,5s)-8)
- (4aRS,5SR,7SR,8aRS)-1-Benzyl-5-(benzylamino)-7-(tert-butyldimethylsilyloxy)-octahydroquinoxaline-2,3-dione (9)
- (4aRS,5SR,7SR,8aRS)-5-Amino-1-benzyl-7-(tert-butyldimethylsilyloxy)-octahydro-quinoxaline-2,3-dione (10)
- (4aRS,5SR,7SR,8aRS)-1-Benzyl-7-(tert-butyldimethylsilyloxy)-5-(pyrrolidin-1-yl)-octahydroquinoxaline-2,3-dione (11)
- 1-[(4aRS,6SR,8SR,8aRS)-4-Benzyl-6-(tert-butyldimethylsilyloxy)-8-(pyrrolidin-1-yl)-decahydroquinoxalin-1-yl]-2-(3,4-dichlorophenyl)ethan-1-one (13)
- 1-[(4aRS,6SR,8SR,8aRS)-4-Benzyl-6-hydroxy-8-(pyrrolidin-1-yl)decahydro-quinoxalin-1-yl]-2-(3,4-dichlorophenyl)ethan-1-one (14)
3.2. Receptor Binding Studies
3.3. Determination of κ Receptor Affinity (Guinea Pig Brain) [22,31]
3.4. Molecular Modeling
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Compd. | X | Ki ± SEM [nM] (a,b) | ||||
---|---|---|---|---|---|---|
κ Receptor | μ Receptor | δ Receptor | σ1 Receptor | σ2 Receptor | ||
[3H]U-69,593 | [3H]DAMGO | [3H]DPDPE | [3H]-(+)-pentazocine | [3H]DTG | ||
2a [22] | H | 9.4 ± 1.6 | 3900 | 39% | 1390 | 4390 |
13 | OTBS | 0% | -- | -- | 487 | 7% |
14 | OH | 599 ± 217 | 0% | 11% | 7900 | 0% |
U-50,488 | 0.34 ± 0.07 | |||||
U-69,593 | 0.88 ± 0.10 | - | - | - | - | |
naloxone | 6.9 ± 0.50 | 2.3 ± 1.1 | 103 | - | - | |
morphine | 35 ± 6 | 5.2 ± 1.6 | - | - | - | |
SNC80 | - | - | 1.2 ± 0.5 | - | - | |
(+)-pentazocine | - | - | - | 5.4 ± 0.5 | - | |
haloperidol | - | - | - | 6.6 ± 0.9 | 78 ± 2.3 |
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Hoffmann, J.; Schepmann, D.; Daniliuc, C.; Bermudez, M.; Wünsch, B. Stereoselective Synthesis and Biological Evaluation of Perhydroquinoxaline-Based κ Receptor Agonists. Int. J. Mol. Sci. 2025, 26, 998. https://doi.org/10.3390/ijms26030998
Hoffmann J, Schepmann D, Daniliuc C, Bermudez M, Wünsch B. Stereoselective Synthesis and Biological Evaluation of Perhydroquinoxaline-Based κ Receptor Agonists. International Journal of Molecular Sciences. 2025; 26(3):998. https://doi.org/10.3390/ijms26030998
Chicago/Turabian StyleHoffmann, Jonathan, Dirk Schepmann, Constantin Daniliuc, Marcel Bermudez, and Bernhard Wünsch. 2025. "Stereoselective Synthesis and Biological Evaluation of Perhydroquinoxaline-Based κ Receptor Agonists" International Journal of Molecular Sciences 26, no. 3: 998. https://doi.org/10.3390/ijms26030998
APA StyleHoffmann, J., Schepmann, D., Daniliuc, C., Bermudez, M., & Wünsch, B. (2025). Stereoselective Synthesis and Biological Evaluation of Perhydroquinoxaline-Based κ Receptor Agonists. International Journal of Molecular Sciences, 26(3), 998. https://doi.org/10.3390/ijms26030998