2 NK-3 RECEPTOR SUBTYPES - DEMONSTRATION BY BIOLOGICAL AND BINDING ASSAYS

The existence of two neurokinin NK-3 receptor subtypes has been suggested on the basis of results obtained in binding assays. In the present study, we have confirmed the two NK-3 receptor subtypes by using data obtained in both biological and binding assays. Experiments have been performed in the rat portal vein and in the guinea-pig ileum treated with NK-1 and NK-2 selective antagonists, namely CP 96345 and SR 48968. Orders of potency of agonists on the rat portal vein are as follows: for neurokinins, NKB > NKA > SP; for tachykinins, KAS > ELE > PHY; and for selective agonist: [MePhe(7)]NKB >> senktide. On the guinea-pig ileum, the agonist rank orders of potency are: NKB > SP > NKA, ELE > KAS > PHY; and for selective agonist: [MePhe(7)]N KB = senktide. The apparent affinity of antagonists shows differences in both biological and binding assays. In fact, on the rat portal vein, SR 48968 is almost inactive (pA(2) or IC50 approximate to 4.8), while R-486 [Trp(7),beta Ala(8)]NKA(4-10) shows a pA(2) value of 7.45 and an IC50 of 5.6. An opposite pattern of activity is observed in the guinea-pig ileum, where SR 48968 shows a pA(2) of 6.05 and an IC50 of 6.7, while R-486 has a pA(2) of 6.1 and an IC50 of < 5.0. These results confirm the existence of two NK-3 sites differing pharmacologically. It is proposed to name NK-3A the receptor of the guineapig ileum and NK-3B the receptor of the rat portal vein.