title: Synthesis and characterization of a disubstituted piperazine derivative with T-type channel blocking action and analgesic properties.
abstract: BACKGROUND
  T-type calcium channels are important contributors to signaling in the primary afferent pain pathway and are thus important targets for the development of analgesics. It has been previously reported that certain piperazine-based compounds such as flunarizine are able to inhibit T-type calcium channels. Thus, we hypothesized that novel piperazine compounds could potentially act as analgesics.
  
  
  RESULTS
  Here, we have created a series of 14 compound derivatives around a diphenyl methyl-piperazine core pharmacophore. Testing their effects on transiently expressed Cav3.2 calcium channels revealed one derivative (3-((4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)methyl)-4-(2-methoxyphenyl)-1,2,5-oxadiazole 2-oxide, compound 10e) as a potent blocker. 10e mediate tonic block of these channels with an IC50 of around 4 micromolar. 10e also blocked Cav3.1 and Cav3.3 channels, but only weakly affected high-voltage-activated Cav1.2 and Cav2.2 channels. Intrathecal delivery of 10e mediated relief from formalin and complete Freund's adjuvant induced inflammatory pain that was ablated by genetic knockout of Cav3.2 channels.
  
  
  CONCLUSIONS
  Altogether, our data identify a novel T-type calcium channel blocker with tight structure activity relationship (SAR) and relevant in vivo efficacy in inflammatory pain conditions.
authors.affiliation: School of Chemical Sciences, SRTM University, Nanded, Maharashtra, India.
authors.forename: Zubaidha
authors.initials: Z
authors.lastname: Pudukulatham
authors.affiliation: Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Fang-Xiong
authors.initials: FX
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Vinicius M
authors.initials: VM
authors.lastname: Gadotti
authors.affiliation: Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Said
authors.initials: S
authors.lastname: M'Dahoma
authors.affiliation: School of Chemical Sciences, SRTM University, Nanded, Maharashtra, India.
authors.forename: Prabhuling
authors.initials: P
authors.lastname: Swami
authors.affiliation: School of Chemical Sciences, SRTM University, Nanded, Maharashtra, India.
authors.forename: Yasinalli
authors.initials: Y
authors.lastname: Tamboli
authors.affiliation: Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada zamponi@ucalgary.ca.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Zamponi
mesh_terms: D059787:Acute Pain / Q000188:drug therapy / Q000503:physiopathology; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D055724:Electrophysiological Phenomena / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D000700:Analgesics; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D010879:Piperazines
keywords: T-type; analgesia; calcium channel; pain; piperazine