Conformationally constrained ethylenediamines: synthesis and receptor binding of 6,8-diazabicyclo[3.2.2]nonanes.
The synthesis and receptor affinity of 6,8-diazabicyclo[3.2.2]nonanes representing conformationally constrained ethylenediamines are described. The Dieckmann analogous cyclization of the (piperazin-2-yl)propionate 9 provided the bicyclononane 10 only, when the first cyclization product was trapped with chlorotrimethylsilane. 10 was stereoselectively transformed into the bicyclic amines 19a,b and amides 22a,b, which were investigated in competition experiments with radioligands for their sigma(1)-, sigma(2)-, kappa-, and mu-receptor affinities. The (2R)-configured dimethylamine 19a showed promising sigma(1)-receptor affinity (K(i)=23.8 nM) and selectivity, whereas the (2S)-configured (dichlorophenyl)acetamide 22b displayed a sigma-receptor binding profile (sigma(1): K(i)=184 nM; sigma(2): K(i)=263 nM) very similar to the binding profile of the atypical antipsychotic BMY-14802 (26).
Weigl
Manuela
M
Pharmazeutisches Institut der Universität Freiburg, Albertstrasse 25, D-79104 Freiburg i. Br., Germany.
Bedürftig
Stephan
S
Maier
Christoph A
CA
Wünsch
Bernhard
B
D000473:Alkanes / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000196:embryology; D001643:Bridged Bicyclo Compounds / Q000378:metabolism*; D005029:Ethylenediamines / Q000138:chemical synthesis* / Q000378:metabolism*; D006168:Guinea Pigs; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism*; D013057:Spectrum Analysis
D000473:Alkanes; D001643:Bridged Bicyclo Compounds; D005029:Ethylenediamines; D011957:Receptors, Opioid; C031234:ethylenediamine; C017573:nonane