Hydroxyalkylation with cyclic sulfates: synthesis of carbazole derived CB(2) ligands with increased polarity.
In order to increase the polarity of the potent CB2 ligand 1a, the homologous hydroxyalkyl carbazoles 2a-c were prepared and pharmacologically evaluated. An important step in the synthesis is the hydroxyalkylation of carbazole with cyclic sulfates providing the 2-hydroxyethyl and 3-hydroxypropyl derivatives 5a and 5b in a one-step reaction. The final propionamides 2a-c were prepared using the recently reported coupling reagent COMU®. The X-ray crystal structure of 2c displays an almost coplanar arrangement of the 3-phenyl-1,2,4-oxadiazole biaryl system. The increased polarity of 2a is associated with an almost 100-fold reduced CB2 affinity. The 3-hydroxypropyl derivative 2b represents the best compromise between lipophilicity and CB2 affinity (Ki  = 33 nM).
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Münster, Germany.
Corinna
C
Lueg
Fabian
F
Galla
Bastian
B
Frehland
Dirk
D
Schepmann
Constantin G
CG
Daniliuc
Winnie
W
Deuther-Conrad
Peter
P
Brust
Bernhard
B
Wünsch
D000478:Alkylation; D000818:Animals; D016466:CHO Cells; D063386:Cannabinoid Receptor Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D006900:Hydroxylation; D008024:Ligands; D015394:Molecular Structure; D011869:Radioligand Assay; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000138:chemical synthesis* / Q000494:pharmacology*; D014162:Transfection
C588309:CNR2 protein, human; D063386:Cannabinoid Receptor Agonists; D002227:Carbazoles; D008024:Ligands; D043885:Receptor, Cannabinoid, CB2; D013431:Sulfates
CB2 receptor ligands; Carbazole derivatives; Cyclic sulfates; Structure affinity relationships; X-ray crystal structure analysis