Design, synthesis, and preliminary pharmacological evaluation of 4-aminopiperidine derivatives as N-type calcium channel blockers active on pain and neuropathic pain.
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.
Teodori
Elisabetta
E
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Via U. Schiff 6, 50019 Sesto Fiorentino (FI), Italy. elisabetta.teodori@unifi.it
Baldi
Elisabetta
E
Dei
Silvia
S
Gualtieri
Fulvio
F
Romanelli
Maria Novella
MN
Scapecchi
Serena
S
Bellucci
Cristina
C
Ghelardini
Carla
C
Matucci
Rosanna
R
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002074:Butanones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000187:drug effects* / Q000378:metabolism; D002552:Cerebral Ventricles / Q000378:metabolism; D015195:Drug Design; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D016716:PC12 Cells; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D017288:Pain Threshold; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
C494559:1-(4-aminopiperidin-1-yl)-4,4-bis(fluorophenyl)butan-1-one; D000700:Analgesics; D002074:Butanones; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D010880:Piperidines; D002118:Calcium