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Publications - Bioorganic Chemistry

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Publications

Holzgrabe, U.; Brandt, W.; Mechanism of Action of the Diazabicyclononanone-type κ-Agonists J. Med. Chem. 46, 1383-1389, (2003) DOI: 10.1021/jm0210360

The 2,4-di-2-pyridyl-3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one 1,5-diester HZ2 was recently found to exhibit high affinity and selectivity to the κ-opioid receptor (KOR) in combination with an unusually long duration of action. Docking of HZ2 to the putative binding site model of the KOR revealed HZ2 to be tightly sitting in the binding pocket. Strong interactions, especially salts bridges between the protonated nitrogens of HZ2 and the glutamic acids 209 and 297, nicely explain the high affinity of HZ2 to the KOR. A formation of a hemiaminal bond between the keto carbonyl group of HZ2 and a lysine residue (Lys200) may explain the long duration of action.
Publications

Holzgrabe, U.; Cambareri, A.; Kuhl, U.; Siener, T.; Brandt, W.; Straßburger, W.; Friderichs, E.; Englberger, W.; Kögel, B.; Haurand, M.; Diazabicyclononanones, a potent class of kappa opioid analgesics Farmaco 57, 531-534, (2002) DOI: 10.1016/S0014-827X(02)01243-0

The 1,5-dimethyl 3,7-diaza-3,7-dimethyl-9-oxo-2,4-di-2-pyridine-bicyclo[3.3.1]nonane-1,5-dicarboxylate, HZ2, has a high and selective affinity for the kappa opioid receptor and an antinociceptive activity comparable to morphine. In addition, it is characterized by a long duration of action and a high oral bioavailability. QSAR studies within series of kappa agonists revealed a chair-boat conformation of a double protonated HZ2 characterized by an almost parallel orientation of the C9 carbonyl group and the N7-H group and at least one aromatic ring to be the pharmacophoric arrangement. Structural variations showed that the pyridine rings in 2 and 4 position can be replaced with p-methoxy-, m-hydroxy- and m-fluoro-substituted phenyl rings. However, all other substituents have to be kept the same for a high affinity to the kappa receptor.
Publications

Holzgrabe, U.; Friderichs, E.; Englberger, W.; Strassberger, W.; Maurand, M.; Brandt, W.; Camberri, A.; Kuhl, U.; Siener, T.; Diazabicyclononanones, a new class of opioid-type analgesics Sci. Cult. 68, 1-4, (2002)

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Publications

Siener, T.; Holzgrabe, U.; Drosihn, S.; Brandt, W.; Conformational and configurational behaviour of κ-agonistic 3,7-diazabicyclo[3.3.1]nonan-9-ones—synthesis, nuclear magnetic resonance studies and semiempirical PM3 calculations J. Chem. Soc., Perkin Trans. 2 1999, 1827-1834, (1999) DOI: 10.1039/A806641H

2,4-Diaryl substituted 3,7-diazabicyclo[3.3.1]nonan-9-one 1,5-diesters were found to have a high affinity for κ-opioid receptors. To develop highly potent analgesics, the purpose of this study was the synthesis and the structural characterisation of the novel 2,4-bis(4-nitrophenyl), 2,4-bis(3-nitrophenyl), 2,4-bis(4-quinolyl), 2,4-bis(2-quinolyl), 2,4-bis(1-naphthyl) and 2,4-bis(2-naphthyl) substituted 3,7-diazabicyclo[3.3.1]nonan-9-one 1,5-diesters by means of NMR spectroscopy and molecular modelling. It could be proved that several derivatives undergo trans–cis-isomerisation of the aromatic rings linked to the rigid skeleton whereas others show rotational isomerisation. Semiempirical quantum-chemical PM3 calculations were performed to analyse the thermodynamic stability of the isomers as well as the mechanism of the trans–cis- or cis–trans-conversion.
Publications

Holzgrabe, U.; Nachtsheim, C.; Siener, T.; Drosihn, S.; Brandt, W.; Opioid-Agonisten und -Antagonisten, Opioid-Rezeptoren Pharmazie 52, 4-22, (1997)

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