882994-24-3Relevant academic research and scientific papers
Relationships between the structure of 6-allyl-6,8-diazabicyclo[3.2.2]nonane derivatives and their σ receptor affinity and cytotoxic activity
Holl, Ralph,Schepmann, Dirk,Gruenert, Renate,Bednarski, Patrick J.,Wuensch, Bernhard
body text, p. 777 - 793 (2009/08/07)
A series of bridged piperazine derivatives was prepared and the affinity toward σ1 and σ2 receptors by means of radioligand binding assays as well as the inhibition of the growth of six human tumor cell lines was investigated. All possible stereoisomers of the 2-hydroxy, 2-methoxy, 2,2-dimethoxy, 2-oxo, and 2-unsubstituted 6,8-diazabicyclo[3.2.2]nonanes were prepared in a chiral pool synthesis starting with (S)- and (R)-glutamate. A Dieckmann analogous cyclization was the key step in the synthesis of the bicyclic framework. The configuration in position 2 was established by a diastereoselective LiBH4 reduction and subsequent Mitsunobu inversion. Structure-affinity relationships demonstrate that substituents in position 2 decrease σ1 receptor affinity which might be due to unfavorable interactions with the σ1 receptor protein. Without a substituent in position 2 high σ1 affinity was obtained (23a ((+)-(1S,5S)-6-allyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane): Ki = 11 nM). Experiments with six human tumor cell lines showed a weak but selective growth inhibition of the human small cell lung cancer cell line A-427 by the methyl ethers ent-16b (IC50 = 18.9 μM), 21a (IC50 = 16.4 μM), ent-21a (IC50 = 20.4 μM), and 21b (IC50 = 27.1 μM) and the unsubstituted compounds 23a and 23b (42% inhibition at 20 μM).
Synthesis and pharmacological evaluation of bicyclic SNC80 analogues with separated benzhydryl moiety
Jung, Bettina,Englberger, Werner,Froehlich, Roland,Schepmann, Dirk,Lehmkuhl, Kirstin,Wuensch, Bernhard
, p. 2870 - 2885 (2008/09/19)
Directed by molecular modeling studies the pharmacophoric benzhydryl moiety of the δ opioid receptor agonist SNC80 was separated and the two phenyl residues were attached to different positions of the conformationally constrained 6,8-diazabicyclo[3.2.2]nonane framework in order to find novel δ agonists. The crucial reaction step in the chiral pool synthesis was the establishment of the three carbon bridge by a Dieckmann analogous cyclization of the allyl and propyl derivatives 6 and 7 to yield the mixed methyl silyl acetals 8 and 9, respectively. Stereoselective Grignard reaction, dehydration, and introduction of the pharmacophoric (N,N-diethylcarbamoylbenzyl) residue led to the designed δ receptor agonists 3, ent-3, and 20 with a double bond in the bicyclic framework. Hydrogenation of the allyl derivative 14 was performed with ammonium formate and Pd/C to yield the saturated ligands 24a and 24b. Removal of the allyl substituent with RhCl3, hydrogenation of the ring system, and re-attachment of the allyl moiety provided the allyl derivatives 4a and 4b. In receptor binding studies with the radioligand [3H]-deltorphine II only ent-3 showed considerable δ receptor affinity (Ki = 740 nM). Since ent-3 also interacts with μ receptors (Ki = 250 nM) it belongs to the very interesting compound class of mixed δ/μ ligands.
Molecular modeling directed synthesis of a bicyclic analogue of the δ opioid receptor agonist SNC 80
Jung, Bettina,Englberger, Werner,Wuensch, Bernhard
, p. 281 - 290 (2007/10/03)
In order to find novel δ opioid receptor agonists, the pharmacophoric benzhydryl moiety of the lead compound SNC 80 (1) was dissected and the phenyl residues were attached to different positions of the 6,8-diazabicyclo[3.2.2] nonane core system (4). The position of the carboxamido group, the stereochemistry, the C3/C4 bond order and the kind and length of the spacer X were considered. The resulting compounds were compared with the four energetically most favourable conformations of SNC 80 by a multifit analysis. These calculations led to the structures 5-10, which fit best to SNC 80. Herein the synthesis of one of these compounds (9) is described. Starting from (S)-glutamate two alternative routes are detailed to obtain the key intermediate 14. A variation of the Dieckmann cyclization, which uses trapping of the first cyclization product with ClSiMe3 provided the mixed acetal 20, which was carefully hydrolyzed to yield the bicyclic ketone 17. Stereoselective addition of phenylmagnesium bromide, dehydration, LiAlH4 reduction and exchange of the N-6 residue afforded the designed compound 9. The affinities of 9 towards δ, μ, κ and ORL1 receptors were determined in receptor binding studies with radioligands. Only moderate receptor affinity was found.
