Ro 46-2005 demonstrates competitive antagonism at both ETA and ETB receptors and inhibits functional responses to ET-1 in vitro.
Dual endothelin antagonism is feasible in vitro; leaves open any cardiovascular therapeutic role pending in vivo and clinical validation.
Ro 46-2005 is a new synthetic non-peptide endothelin (ET) receptor antagonist. In binding experiments, Ro 46-2005 proved to be equipotent (IC50 200-500 nM) for inhibition of [125]ET-1 binding on the two known ET receptor subtypes (ETA and ETB). Scatchard analysis was consistent with a competitive binding mode. Ro 46-2005 also inhibited the functional consequences of ET-1 stimulation: the ET-1 induced release of arachidonic acid from rat mesangial cells was inhibited with an IC50 of 1.8 microM.
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Breu et al. (1993) studied this question.
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