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Updated: Jul 5, 2026
14:55
Direct Intraventricular Delivery of Drugs to the Rodent Central Nervous System
Published on: May 12, 2013
Novel ORL1-selective antagonists with oral bioavailability and brain penetrability
Osamu Okamoto1, Kensuke Kobayashi, Hiroshi Kawamoto
1Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Okubo-3, Tsukuba, Ibaraki 300-2611, Japan. osamu_okamoto@merck.com
Bioorganic & Medicinal Chemistry Letters
|May 2, 2008
Summary
Researchers developed a novel, orally available ORL1 antagonist with high potency and selectivity. This brain-penetrant compound, 2-(tert-butylthio)-5-chloro-6-[(2R)-4-(2-hydroxyethyl)-2-methylpiperazin-1-yl]-1H-benzimidazole, resulted from optimizing a benzimidazole lead structure.
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Pharmacology
Background:
- 5-chloro-6-[piperazin-1-yl]-1H-benzimidazole identified as a novel pharmacophore.
- This structure demonstrated potent and selective ORL1 antagonist activity.
Purpose of the Study:
- To optimize the lead benzimidazole structure for improved pharmacological properties.
- To develop a potent, selective, orally available, and brain-penetrant ORL1 antagonist.
Main Methods:
- Introduction of a methyl substitution on the piperazine ring of the lead compound.
- Stereochemical analysis of the methyl substituent to modulate opioid receptor activity.
Main Results:
- A highly potent and selective ORL1 antagonist, 2-(tert-butylthio)-5-chloro-6-[(2R)-4-(2-hydroxyethyl)-2-methylpiperazin-1-yl]-1H-benzimidazole, was synthesized.
- The compound exhibited oral bioavailability and brain penetrability.
- Stereochemistry influenced functional activity at other opioid receptors.
Conclusions:
- The optimized benzimidazole derivative represents a promising candidate for ORL1 antagonist applications.
- Stereoselective synthesis is crucial for fine-tuning activity across opioid receptor subtypes.
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