PubMed 21112782

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Kv11.1 , Kv8.2

Title: The identification, and optimisation of hERG selectivity, of a mixed NET/SERT re-uptake inhibitor for the treatment of pain.

Authors: Derek Angus, Matilda Bingham, Dawn Buchanan, Neil Dunbar, Linsday Gibson, Richard Goodwin, Anders Haunsø, Andrea Houghton, Margaret Huggett, Richard Morphy, Susan Napier, Olaf Nimz, Joanna Passmore, Glenn Walker

Journal, date & volume: , 2010 Nov 6 , ,

PubMed link:

Hit compound 1, a selective noradrenaline re-uptake transporter (NET) inhibitor was optimised to build in potency at the serotonin re-uptake transporter (SERT) whilst maintaining selectivity against the dopamine re-uptake transporter (DAT). During the optimisation of 1 it became clear that selectivity against the Kv11.1 potassium ion channel (hERG) was also a parameter for optimisation within the series. Discrete structural changes to the molecule as well as a lowering of global cLogP successfully increased the hERG selectivity to afford compound 11 m, which was efficacious in a mouse model of inflammatory pain, complete Freund's adjuvant (CFA) induced thermal hyperalgesia and a rat model of neuropathic pain, spinal nerve ligation (SNL) induced mechanical allodynia.