GR138676, A NOVEL PEPTIDIC TACHYKININ ANTAGONIST WHICH IS POTENT AT NK3 RECEPTORS

GR138676, a conformationally constrained analogue of neurokinin B, is a novel, potent NK3 receptor antagonist. GR138676 was a competitive an tagonist of neurokinin B-dependent arachidonic acid mobilization from prelabelled Chinese hamster ovary cells stably transfected with a huma n NK3 receptor gene (pK(B) 8.3) and of contractions induced by senktid e in rat portal vein (pK(B) 8.2). However, GR138676 was also a competi tive antagonist of the increase in intracellular calcium evoked by the selective NK1 agonist, GR73632, in the human astrocytoma U373MG cell- line (pK(B) 8.3). GR138676 had little activity at NK2 receptors, inhib iting binding of the NK2 antagonist radioligand [H-3]-GR100679 to Chin ese hamster ovary cells transfected with the human ileum NK2 receptor with a pKi of 6.0. In summary, despite its activity at NK1 receptors, GR138676 will be a useful tool for characterizing NK3 receptors as wel l as defining the physiological and pathophysiological function of thi s receptor subtype.