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

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 9; pp. 2519 - 2523
• Main Authors: Ho, Ginny D., Anthes, John, Bercovici, Ana, Caldwell, John P., Cheng, Kuo-Chi, Cui, Xiaoming, Fawzi, Ahmad, Fernandez, Xiomara, Greenlee, William J., Hey, John, Korfmacher, Walter, Lu, Sherry X., McLeod, Robbie L., Ng, Fay, Torhan, April Smith, Tan, Zheng, Tulshian, Deen, Varty, Geoffrey B., Xu, Xiaoying, Zhang, Hongtao
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.05.2009; Elsevier
• Subjects: Animals; Anti-Anxiety Agents - chemical synthesis; Anti-Anxiety Agents - pharmacology; Antitussive activity; Antitussive Agents - chemical synthesis; Antitussive Agents - pharmacology; Anxiety - drug therapy; Anxiolytic-like activity; Biological and medical sciences; Capsaicin - chemistry; Capsaicin-induced cough model in guinea pigs; Chemistry, Pharmaceutical - methods; Conditioned lick suppression (CLS) model in rats; Cough - drug therapy; Drug Design; Guinea Pigs; Human pregnane X receptor (hPXR); Humans; Ligands; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Nociceptin receptor; Nociceptin/orphanin FQ (N/OFQ); Opioid receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Receptors, Opioid - chemistry; Receptors, Steroid - chemistry; Separation-induced guinea pig pups vocalization assay (GPPV); Structure-Activity Relationship; Tropanes - chemical synthesis; Tropanes - pharmacology; Human pregnane X receptor (hPXR); Conditioned lick suppression (CLS) model in rats; Capsaicin-induced cough model in guinea pigs; Opioid receptors; Antitussive activity; Anxiolytic-like activity; Nociceptin/orphanin FQ (N/OFQ); Nociceptin receptor; Separation-induced guinea pig pups vocalization assay (GPPV); Rat; Ligand; Psychotropic; Alkaloid; Chlorine Organic compounds; Anxiety; Chemical synthesis; Rodentia; Oral administration; Antitussive agent; In vitro; Biological activity; Tropane derivatives; Cough; In vivo; Vertebrata; Mammalia; Tranquillizer; N/OFQ receptor; Animal; Carboxamide; Models; Fluorine Organic compounds; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.03.031

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 μ 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.