Synthesis and structure--activity relationships of fused imidazopyridines: a new series of benzodiazepine receptor ligands.

Abstract

2-Arylimidazo[4,5-c]quinolines and analogous fused imidazopyridines were synthesized and evaluated as benzodiazepine receptor ligands. Affinity to the receptors was greatly affected by the bulkiness of the aryl group at the 2-position, compared to the pyrazoloquinolines such as CGS-9896. Derivatives with an isoxazole moiety at the 2-position showed high binding affinity and in vivo activity. In the imidazo[4,5-c]quinoline series, substitution at the 6-position decreased or abolished activity. Most derivatives with an unsubstituted isoxazolyl group showed antagonist or inverse agonist activity except for the 7-halo analogues, which exhibited agonist activity. On the other hand, 5-methylisoxazol-3-yl or 3-methylisoxazol-5-yl derivatives generally exhibited agonist activity. A similar substitution effect on the isoxazole moiety was observed in the imidazopyridines fused with a nonaromatic ring. From the detailed pharmacological evaluation, S-8510, 2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano++ +[4,3-b]pyridine monophosphate, possessing weak inverse agonist activity was selected as a therapeutic candidate for the treatment of some symptoms of senile dementia.

• Authors: S Takada, T Sasatani, N Chomei, M Adachi, T Fujishita, M Eigyo, S Murata, K Kawasaki, A Matsushita
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 39 Issue 14 Pg. 2844-51 (Jul 05 1996) ISSN: 0022-2623 [Print] United States
• PMID: 8709114 (Publication Type: Journal Article)

Chemical References

• Anticonvulsants
• GABA-A Receptor Agonists
• GABA-A Receptor Antagonists
• Imidazoles
• Ligands
• Pyridines
• Quinolines
• Receptors, GABA-A
• Diazepam

Topics

• Animals
• Anticonvulsants (chemical synthesis, metabolism, pharmacology)
• Diazepam (metabolism)
• GABA-A Receptor Agonists
• GABA-A Receptor Antagonists
• Imidazoles (chemical synthesis, metabolism, pharmacology)
• Ligands
• Male
• Mice
• Pyridines (chemical synthesis, metabolism, pharmacology)
• Quinolines (chemical synthesis, metabolism, pharmacology)
• Rats
• Rats, Wistar
• Receptors, GABA-A (metabolism)
• Structure-Activity Relationship