GR138676, a novel peptidic tachykinin antagonist which is potent at NK 3 receptors

Abstract

GR138676, a conformationally constrained analogue of neurokinin B, is a novel, potent NK 3 receptor antagonist. GR138676 was a competitive antagonist of neurokinin B-dependent arachidonic acid mobilization from prelabelled Chinese hamster ovary cells stably transfected with a human NK 3 receptor gene (pK B 8.3) and of contractions induced by senktide in rat portal vein (pK B 8.2). However, GR138676 was also a competitive antagonist of the increase in intracellular calcium evoked by the selective NK 1 agonist, GR73632, in the human astrocytoma U373MG cell-line (pK B 8.3). GR138676 had little activity at NK 2 receptors, inhibiting binding of the NK 2 antagonist radioligand [ 3H]-GR100679 to Chinese hamster ovary cells transfected with the human ileum NK 2 receptor with a pKi of 6.0. In summary, despite its activity at NK 1 receptors, GR138676 will be a useful tool for characterizing NK 3 receptors as well as defining the physiological and pathophysiological function of this receptor subtype.