Receptor-selective, peptidase-resistant agonists at neurokinin NK-1 and NK-2 receptors: new tools for investigating neurokinin function.
The pharmacological profiles of two novel neurokinin agonists have been investigated. delta Ava[L-Pro9,N-MeLeu10]SP(7-11) (GR73632) and [Lys3,Gly8-R-gamma-lactam-Leu9] NKA(3-10) (GR64349) are potent and selective agonists at NK-1 and NK-2 receptors respectively. In the guinea-pig isolated trachea preparation, contractions induced by these agonists were largely unaffected by inclusion of peptidase inhibitors in the bathing medium, indicating that these agonists are resistant to metabolism by peptidases. In the anaesthetised guinea-pig, both agonists were more potent bronchoconstrictor agents than either NKA or the SP analogue, SP methylester. In the anaesthetised rat, the NK-1 agonist, GR73632 was more potent than SP, NKA or NKB at causing the histamine-independent extravasation of plasma proteins into the skin after intradermal administration. The NK-2 agonist, GR64349 and the NK-3 agonist, senktide were without significant effect in this model. These agonists are useful tools for characterizing neurokinin receptor-mediated actions both in vitro and in vivo.
Hagan
R M
RM
Department of Neuropharmacology, Glaxo Group Research Ltd, Ware, Hertfordshire.
Ireland
S J
SJ
Jordan
C C
CC
Beresford
I J
IJ
Deal
M J
MJ
Ward
P
P
D000279:Administration, Cutaneous; D000595:Amino Acid Sequence; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D002199:Capillary Permeability / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D006168:Guinea Pigs; D008297:Male; D008969:Molecular Sequence Data; D015288:Neurokinin A / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D015287:Neurokinin B / Q000031:analogs & derivatives / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D018039:Receptors, Tachykinin; D013373:Substance P / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects
D010446:Peptide Fragments; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; C054724:senktide; C068032:GR 73632; C068031:neurokinin A (3-10), lysyl(3)-glycyl(8)-R-lactam-leucine(9)-; D013373:Substance P; C033611:substance P, methyl ester-; D015288:Neurokinin A; D015287:Neurokinin B; C056408:neurokinin A(4-10)