Design, synthesis, and preliminary biological evaluation of new isoform-selective f-current blockers.
New I(f) blockers have been designed and tested on HEK293 cells stably expressing the HCN1, HCN2, and HCN4 channels to find compounds able to discriminate among the channel isoforms. Among the synthesized compounds, the cis-butene derivative (R)-5 shows some preference for HCN2 while the pseudodimeric product (R)-6 shows selectivity for HCN1. These compounds can be important pharmacological tools to study the channels in native tissues and may be useful to design safe drugs.
Melchiorre
Michele
M
Laboratory of Design, Synthesis, and Study of Biologically Active Heterocycles (HeteroBioLab), Department of Pharmaceutical Sciences, Via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy.
Del Lungo
Martina
M
Guandalini
Luca
L
Martini
Elisabetta
E
Dei
Silvia
S
Manetti
Dina
D
Scapecchi
Serena
S
Teodori
Elisabetta
E
Sartiani
Laura
L
Mugelli
Alessandro
A
Cerbai
Elisabetta
E
Romanelli
Maria Novella
MN
D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D066298:In Vitro Techniques; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D051379:Mice; D009124:Muscle Proteins / Q000037:antagonists & inhibitors*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels; D011437:Propylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013268:Stimulation, Chemical
D001552:Benzazepines; D054815:Cyclic Nucleotide-Gated Cation Channels; C578665:HCN1 protein, human; C578710:HCN2 protein, human; C119587:HCN4 protein, human; C578666:Hcn1 protein, mouse; C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009124:Muscle Proteins; C552713:N,N-bis(4-(7,8-dimethoxy-2-oxo-1,3-dihydrobenzo(d)azepin-3-yl)but-2-enyl)-2-(3,4-dimethoxyphenyl)propanamine; D015221:Potassium Channels; D011437:Propylamines; D020033:Protein Isoforms