Synthesis, pharmacology, and structure-activity relationships of novel imidazolones and pyrrolones as modulators of GABAA receptors.
New series of imidazolones and pyrrolones were synthesized. The compounds were tested regarding their anxiolytic properties due to modulation of the GABAA receptor response. Several derivatives exhibit considerable pharmacological activity while lacking the typical side effects of benzodiazepine receptor agonists. 1-(4-chlorophenyl)-4-morpholin-1-yl-1,5-dihydro-imidazol-2-one (2) and 1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-one (3) were protective in the pentylenetetrazole test in rats with oral ED50 of 27.4 and 12.8 mg/kg and TD50 (rotarod) of >500 and 265 mg/kg, respectively. The minimum effective dose in the Vogel conflict test was 3 mg/kg for both compounds. Common structure-activity relationship and comparative molecular field analysis models of the various series of derivatives could be established which are in accordance with a GABAA mediated pharmacological action. The findings fit well into an established pharmacophore model. This model is refined by an additional steric restriction feature.
elbion AG, Meissner Strasse 191, D-01445 Radebeul, Germany, and Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, University of Leipzig, Brüderstrasse 34, D-04103 Leipzig, Germany. christian.grunwald@elbion.de
Christian
C
Grunwald
Chris
C
Rundfeldt
Hans-Joachim
HJ
Lankau
Thomas
T
Arnold
Norbert
N
Höfgen
Rita
R
Dost
Ute
U
Egerland
Hans-Jörg
HJ
Hofmann
Klaus
K
Unverferth
D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D000927:Anticonvulsants / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D007093:Imidazoles / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009025:Morpholines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D010433:Pentylenetetrazole; D010880:Piperidines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D011758:Pyrroles / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D045442:Rotarod Performance Test; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy
C509856:1-(4-chlorophenyl)-4-morpholin-1-yl-1,5-dihydroimidazol-2-one; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D007093:Imidazoles; D009025:Morpholines; D010880:Piperidines; D011758:Pyrroles; C504151:1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydroimidazol-2-one; D010433:Pentylenetetrazole