1,4-Diazepanes derived from (S)-serine--homopiperazines with improved sigma(1) (sigma) receptor affinity and selectivity.
Starting from the proteinogenic amino acid (S)-serine chiral non-racemic 1,4-diazepanes 4 with a hydroxymethyl residue in position 2 are synthesized and pharmacologically evaluated. The key step in the synthesis is the formation of the bicyclic system 8 by consecutive nucleophilic substitution of the chloropropionamide 7 with primary amines and intramolecular aminolysis. Both reaction steps require catalysis with the Lewis acid Ti(O-iPr)4. Homologation of the piperazine to the 1,4-diazepane ring results in a remarkable improvement of sigma(1) receptor affinity and sigma(1)/sigma(2) selectivity. The 1,4-dibenzyl derivative 4a interacts with a K(i) value of 7.4 nM with sigma(1) receptors and shows a 53-fold selectivity for sigma(1) receptors over sigma(2) receptors.
Bedürftig
Stephan
S
Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Iniversität Münster, Hittorfstrasse 58-62, 48149 Münster, Germany.
Wünsch
Bernhard
B
D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry; D011485:Protein Binding; D017480:Receptors, sigma / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001381:Azepines; D010879:Piperazines; D017480:Receptors, sigma; D000077489:Piperazine