NR2B-selective N-methyl-D-aspartate antagonists: synthesis and evaluation of 5-substituted benzimidazoles.

Abstract

Two classes of 5-substituted benzimidazoles were identified as potent antagonists of the NR2B subtype of the N-methyl-d-aspartate (NMDA) receptor. Selected compounds show very good selectivity versus the NR2A, NR2C, and NR2D subtypes of the NMDA receptor as well as versus hERG-channel activity and alpha(1)-adrenergic binding. Benzimidazole 37a shows excellent activity in the carrageenan-induced mechanical hyperalgesia assay in rats as well as good pharmacokinetic behavior in dogs.

• Authors: John A McCauley, Cory R Theberge, Joseph J Romano, Susan B Billings, Kenneth D Anderson, David A Claremon, Roger M Freidinger, Rodney A Bednar, Scott D Mosser, Stanley L Gaul, Thomas M Connolly, Cindra L Condra, Menghang Xia, Michael E Cunningham, Bohumil Bednar, Gary L Stump, Joseph J Lynch, Alison Macaulay, Keith A Wafford, Kenneth S Koblan, Nigel J Liverton
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 47 Issue 8 Pg. 2089-96 (Apr 08 2004) ISSN: 0022-2623 [Print] United States
• PMID: 15056006 (Publication Type: Journal Article)

Chemical References

• Analgesics
• Benzimidazoles
• NR2B NMDA receptor
• Receptors, N-Methyl-D-Aspartate
• Carrageenan
• Calcium

Topics

• Analgesics (chemical synthesis, pharmacokinetics, pharmacology)
• Animals
• Benzimidazoles (chemical synthesis, pharmacokinetics, pharmacology)
• Brain (metabolism)
• Calcium (metabolism)
• Carrageenan
• Cell Line
• Dogs
• Female
• Humans
• Hyperalgesia (blood, chemically induced, drug therapy)
• In Vitro Techniques
• Male
• Patch-Clamp Techniques
• Rats
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors, physiology)
• Structure-Activity Relationship