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 receptor has been recently proposed. In the rat isolated urinary bladder, the non-peptide NK1 receptor antagonist RP 67,580 exhibits a higher affinity towards septide (pKB 7.57) than towards [Sar9]substance P sulfone (pKB 7.00). In this study we have investigated the pharmacological profile of the non-mammalian tachykinin physalaemin, of the synthetic NK1 receptor agonist GR 73,632 (delta-aminovaleryl[LPro9,NMeLeu10]substance P(7-11)) and of [Glu(OBzl)11]substance P in relation to the putative existence of a septide-sensitive receptor. The activity of [Glu(OBzl)11]substance P at the NK1, NK2 and NK3 receptor was assayed in the guinea-pig ileum NK1 receptor assay (EC50 26 nM), in the rabbit pulmonary artery NK2 receptor assay (weak agonist activity) and in the rat portal vein NK3 receptor assays (no appreciable activity up to 1 microM). GR 73,632, [Glu(OBzl)11]substance P and physalaemin, all produced concentration-dependent contractions of the rat isolated urinary bladder, with EC50 values of 17, 79, and 9 nM, respectively. The responses to the three agonists were very slightly or not modified by the NK2 receptor antagonist SR 48,968 (1 microM). RP 67,580 (0.3-3 microM) produced a concentration-dependent rightward shift of the curve to GR 73,632, [Glu(OBzl)11]substance P and physalaemin without producing depression of their maximal response. Schild plot analysis indicated the competitive nature of the antagonism. The affinity (pKB) of RP 67,580 towards physalaemin, GR 73,632 and [Glu(OBzl)11]substance P was 7.12, 7.56 and 7.95, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Meini
S
S
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Patacchini
R
R
Lecci
A
A
Poulos
C
C
Rovero
P
P
Maggi
C A
CA
D000818:Animals; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000032:analysis*; D006168:Guinea Pigs; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D010803:Physalaemin / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D018039:Receptors, Tachykinin / Q000819:agonists*; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001743:Urinary Bladder / Q000187:drug effects*
D010446:Peptide Fragments; D018039:Receptors, Tachykinin; C068032:GR 73632; D010803:Physalaemin; D013373:Substance P; D018698:Glutamic Acid