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

The existence of two neurokinin NK-3 receptor subtypes has been sugges ted 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; an d for selective agonist: [MePhe(7)]NKB >> senktide. On the guinea-pig ileum, the agonist rank orders of potency are: NKB > SP > NKA, ELE > K AS > PHY; and for selective agonist: [MePhe(7)]N KB = senktide. The ap parent affinity of antagonists shows differences in both biological an d 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 op posite 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 p A(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 th e rat portal vein.