Identification of 3-substituted N-benzhydryl-nortropane analogs as nociceptin receptor ligands for the management of cough and anxiety

Shu-Wei Yang; Ginny Ho; Deen Tulshian; William J Greenlee; Zheng Tan; Hongtao Zhang; April Smith-Torhan; Ahmad Fawzi; John Anthes; Sherry Lu; Geoffrey Varty; Xiomara Fernandez; Robbie L McLeod; John Hey

doi:10.1016/j.bmcl.2009.03.057

Identification of 3-substituted N-benzhydryl-nortropane analogs as nociceptin receptor ligands for the management of cough and anxiety

Bioorg Med Chem Lett. 2009 May 1;19(9):2482-6. doi: 10.1016/j.bmcl.2009.03.057. Epub 2009 Mar 18.

Authors

Shu-Wei Yang¹, Ginny Ho, Deen Tulshian, William J Greenlee, Zheng Tan, Hongtao Zhang, April Smith-Torhan, Ahmad Fawzi, John Anthes, Sherry Lu, Geoffrey Varty, Xiomara Fernandez, Robbie L McLeod, John Hey

Affiliation

¹ Department of Chemical Research-CV & CNS, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.

PMID: 19332374
DOI: 10.1016/j.bmcl.2009.03.057

Abstract

A series of nortropane analogs based on previously reported compound 1 have been synthesized and shown to bind to the nociceptin receptor with high affinity. The synthesis and structure-activity relationships around the C-3 nortropane substitution are described. From the SAR study and hPXR screening effort, compound 15 was identified to possess potent oral antitussive and anxiolytic-like activities in the guinea pig models.

MeSH terms

Administration, Oral
Animals
Anti-Anxiety Agents / pharmacology
Antitussive Agents / pharmacology
Anxiety / drug therapy*
Chemistry, Pharmaceutical / methods*
Cough / drug therapy*
Drug Design
Guinea Pigs
Kinetics
Ligands
Molecular Structure
Nociceptin Receptor
Nortropanes / chemical synthesis*
Nortropanes / pharmacology
Receptors, Opioid / chemistry
Receptors, Opioid / metabolism*
Structure-Activity Relationship

Substances

Anti-Anxiety Agents
Antitussive Agents
Ligands
Nortropanes
Receptors, Opioid
Nociceptin Receptor