The discovery of tropane derivatives as nociceptin receptor ligands for the management of cough and anxiety.

Abstract

The discovery of 1 as a high-affinity ligand for the nociceptin receptor has led to the synthesis of a series of tropane (8-methyl-8-azabicyclo[3.2.1]octane) derivatives as optimized ligands. These compounds exhibit high affinity for the nociceptin receptor, moderate to excellent selectivity over the opioid mu receptor, and behave as full agonists. In this Letter, we present the synthesis and highlight the structure-activity relationship of tropane derivatives culminating in the identification of 24 and 32 as potent and orally active antitussive and anxiolytic agents. The in vitro and in vivo activities, pharmacokinetic profile, and the hPXR activity, which predicts the potential 3A4 induction in human, are disclosed.

• Authors: Ginny D Ho, John Anthes, Ana Bercovici, John P Caldwell, Kuo-Chi Cheng, Xiaoming Cui, Ahmad Fawzi, Xiomara Fernandez, William J Greenlee, John Hey, Walter Korfmacher, Sherry X Lu, Robbie L McLeod, Fay Ng, April Smith Torhan, Zheng Tan, Deen Tulshian, Geoffrey B Varty, Xiaoying Xu, Hongtao Zhang
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 19 Issue 9 Pg. 2519-23 (May 01 2009) ISSN: 1464-3405 [Electronic] England
• PMID: 19339177 (Publication Type: Journal Article)

Chemical References

• Anti-Anxiety Agents
• Antitussive Agents
• Ligands
• Pregnane X Receptor
• Receptors, Opioid
• Receptors, Steroid
• Tropanes
• Capsaicin
• Nociceptin Receptor

Topics

• Animals
• Anti-Anxiety Agents (chemical synthesis, pharmacology)
• Antitussive Agents (chemical synthesis, pharmacology)
• Anxiety (drug therapy)
• Capsaicin (chemistry)
• Chemistry, Pharmaceutical (methods)
• Cough (drug therapy)
• Drug Design
• Guinea Pigs
• Humans
• Ligands
• Pregnane X Receptor
• Receptors, Opioid (chemistry)
• Receptors, Steroid (chemistry)
• Structure-Activity Relationship
• Tropanes (chemical synthesis, pharmacology)
• Nociceptin Receptor