Synthesis and NMDA receptor affinity of fluorinated dioxadrol analogues.
A series of dioxadrol analogues with fluorine substituents in position 4 of the piperidine ring has been synthesized and pharmacologically evaluated. The key step in the synthesis was the fluorination of diastereomeric piperidones 6a and 6c as well as diastereomeric alcohols 9a and 9c with DAST. The reaction of the alcohols 9a and 9c took place with inversion of configuration. After removal of the Cbz-protective group, the NMDA receptor affinities of the resulting secondary amines 8a, 8c, 12b, and 12d were investigated in receptor binding studies. It was shown that the like-configuration of the ring junction was crucial for high NMDA receptor affinity. An axially oriented fluorine atom in position 4 led to 2-(2,2-diphenyl-1,3-dioxolan-4-yl)-4-fluoropiperidine (12d, WMS-2517) with a K(i)-value of 27nM. The NMDA receptor affinity of 8c (WMS-2513) with an additional fluorine atom in equatorial 4-position was slightly reduced (K(i)=81 nM). Both fluorinated dioxadrol derivatives 8c and 12d showed high selectivity against sigma(1) and sigma(2) receptors as well as the polyamine binding site of NR2B receptors.
Banerjee
Ashutosh
A
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhems-Universität Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.
Schepmann
Dirk
D
Wünsch
Bernhard
B
D000438:Alcohols / Q000737:chemistry; D000588:Amines; D000700:Analgesics / Q000138:chemical synthesis*; D001665:Binding Sites; D004148:Dioxolanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054879:Halogenation; D006801:Humans; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010881:Piperidones / Q000737:chemistry; D011485:Protein Binding; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000438:Alcohols; D000588:Amines; D000700:Analgesics; D004148:Dioxolanes; D010880:Piperidines; D010881:Piperidones; D016194:Receptors, N-Methyl-D-Aspartate; C005840:dioxadrol