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Investigation of connexin 43 uncoupling and prolongation of the cardiac QRS complex in preclinical and marketed drugs
Author(s) -
Burnham M P,
Sharpe P M,
Garner C,
Hughes R,
Pollard C E,
Bowes J
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12554
Subject(s) - pharmacology , qrs complex , gap junction , ic50 , connexin , drug , sodium channel , medicine , qt interval , chemistry , biochemistry , sodium , in vitro , organic chemistry , intracellular
Background and Purpose Prolongation of the cardiac QRS complex is linked to increased mortality and may result from drug‐induced inhibition of cardiac sodium channels ( hNa V 1 .5). There has been no systematic evaluation of preclinical and marketed drugs for their additional potential to cause QRS prolongation via gap junction uncoupling. Experimental Approach Using the human cardiac gap junction connexin 43 (hCx43), a dye transfer ‘parachute’ assay to determine IC 50 values for compound ranking was validated with compounds known to uncouple gap junctions. Uncoupling activity (and hNa V 1 .5 inhibition by automated patch clamp) was determined in a set of marketed drugs and preclinical candidate drugs, each with information regarding propensity to prolong QRS . Key Results The potency of known gap junction uncouplers to uncouple hCx43 was ranked (according to IC 50 ) as phorbol ester>digoxin>meclofenamic acid>carbenoxolone>heptanol. Among the drugs associated with QRS prolongation, 29% were found to uncouple hCx43 ( IC 50 < 50 μM), whereas no uncoupling activity was observed in drugs not associated with QRS prolongation. In preclinical candidate drugs, hCx43 and hNa V 1.5 IC 50 values were similar (within threefold). No consistent margin over preclinical C max (free) was apparent for QRS prolongation associated with Cx43 inhibition. However, instances were found of QRS prolonging compounds that uncoupled hCx43 with significantly less activity at hNa V 1 .5. Conclusion and Implications These results demonstrate that off‐target uncoupling activity is apparent in drug and drug‐like molecules. Although the full ramifications of C x inhibition remain to be established, screening for hCx43 off‐target activity could reduce the likelihood of developing candidate drugs with a risk of causing QRS prolongation.