GR-73,632 AND [GLU(OBZL)(11)]SUBSTANCE-P ARE SELECTIVE AGONISTS FOR THE SEPTIDE-SENSITIVE TACHYKININ NK1 RECEPTOR IN THE RAT URINARY-BLADDER

The existence of a septide-sensitive subtype of the tachykinin NK1 rec eptor has been recently proposed. In the rat isolated urinary bladder, the non-peptide NK1 receptor antagonist RP 67,580 exhibits a higher a ffinity towards septide (pK(B) 7.57) than towards [Sar(9)]substance P sulfone (pK(B) 7.00). In this study we have investigated the pharmacol ogical profile of the nonmammalian tachykinin physalaemin, of the synt hetic NK1 receptor agonist GR 73,632 (delta-aminovaleryl[LPro(9),NMeLe u(10)]substance P(7-11)) and of [Glu(OBzl)(11)]substance P in relation to the putative existence of a septide-sensitive receptor. The activi ty of [Glu(OBzl)(11)]substance P at the NK1, NK2 and NK3 receptor was assayed in the guinea-pig ileum NK1 receptor assay (EC(50) 26 nM), in the rabbit pulmonary artery NK2 receptor assay (weak agonist activity) and in the rat portal vein NK3 receptor assays (no appreciable activi ty up to 1 mu M). GR 73,632, [Glu(OBzl)(11)]substance P and physalaemi n, all produced concentration-dependent contractions of the rat isolat ed urinary bladder, with EC(50) values of 17, 79, and 9 nM, respective ly. The responses to the three agonists were very slightly or not modi fied by the NK2 receptor antagonist SR 48,968 (1 mu M). RP 67,580 (0.3 -3 mu M) produced a concentration-dependent rightward shift of the cur ve to GR 73,632, [Glu(OBzl)(11)]substance P and physalaemin without pr oducing depression of their maximal response. Schild plot analysis ind icated the competitive nature of the antagonism. The affinity (pK(B)) of RP 67,580 towards physalaemin, GR 73,632 and [Glu(OBzl)(11)]substan ce P was 7.12, 7.56 and 7.95, respectively. These findings indicate th at the C-terminal derivative of substance P GR 73,632 and the undecape ptide [Glu(OBzl)(11)]substance P preferentially stimulate the septide- sensitive NK1 receptor in the rat urinary bladder, suggesting that the N-terminal sequence of substance P does not necessarily contribute to a preferential interaction with the 'classical NK1' receptor. [Glu(OB zl)(11)]substance P appears as a better ligand than septide itself at the septide-sensitive NK1 receptor.