Design, synthesis, and preliminary pharmacological evaluation of 4-aminopiperidine derivatives as N-type calcium channel blockers active on pain and neuropathic pain.

Abstract

Several compounds with a 4-aminopiperidine scaffold decorated on both nitrogen atoms by alkyl or acyl moieties containing the structural motifs of verapamil and of flunarizine, as well as those that are more frequent in known N-type calcium channel antagonists, have been synthesized. Antinociceptive activity on the mouse hot-plate test was used to select molecules to be submitted to further studies. Active compounds were tested in vitro on a PC12 rat pheochromocytoma clonal cell line, to evaluate their action on N-type calcium channels, and on a rat model of neuropathic pain. Two compounds that show N-type calcium channel antagonism and are endowed with potent action on pain and neuropathic pain (3 and 18) have been selected for further studies.

• Authors: Elisabetta Teodori, Elisabetta Baldi, Silvia Dei, Fulvio Gualtieri, Maria Novella Romanelli, Serena Scapecchi, Cristina Bellucci, Carla Ghelardini, Rosanna Matucci
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 47 Issue 24 Pg. 6070-81 (Nov 18 2004) ISSN: 0022-2623 [Print] United States
• PMID: 15537361 (Publication Type: Journal Article)

Chemical References

• 1-(4-aminopiperidin-1-yl)-4,4-bis(fluorophenyl)butan-1-one
• Analgesics
• Butanones
• Calcium Channel Blockers
• Calcium Channels, N-Type
• Piperidines
• Calcium

Topics

• Analgesics (chemical synthesis, chemistry, pharmacology)
• Animals
• Binding Sites
• Butanones (chemical synthesis, chemistry, pharmacology)
• Calcium (metabolism)
• Calcium Channel Blockers (chemical synthesis, chemistry, pharmacology)
• Calcium Channels, N-Type (drug effects, metabolism)
• Cerebral Ventricles (metabolism)
• Drug Design
• In Vitro Techniques
• Male
• Mice
• PC12 Cells
• Pain (drug therapy)
• Pain Measurement
• Pain Threshold
• Peripheral Nervous System Diseases (drug therapy)
• Piperidines (chemical synthesis, chemistry, pharmacology)
• Radioligand Assay
• Rats
• Rats, Sprague-Dawley
• Structure-Activity Relationship