Pharmacological characterisation of NK1 receptor antagonist, [D-Trp7]sendide, on behaviour elicited by substance P in the mouse.
An analogue of sendide, [D-Trp7]sendide, was newly synthetized and evaluated as a putative NK1 receptor antagonist in a mouse behavioural test. Effects of [D-Trp7]sendide on the scratching, biting and licking response induced by substance P (SP), neurokinin A (NK A) and neurokinin B (NK B) was studied after intrathecal injections. When administered simultaneously with SP, an endogenous agonist for NK1 receptors, [D-Trp7]sendide inhibited the behavioural response to this tachykinin in a dose-dependent manner with ID50 value of 11.0 pmol/mouse. The behavioural response elicited by other NK1 receptor agonists, septide and physalaemin, was reduced significantly by a small dose (32.0 pmol) of [D-Trp7]sendide. Large doses (nmol order) of [D-Trp7]sendide were needed to reduce the characteristic behaviour of NK A, an NK2 agonist, NK B, an NK3 agonist and eledoisin, an NK2/NK3 agonist. The duration of the antagonistic effect of [D-Trp7]sendide was relatively longer. In a [3H]labeled SP binding assay using mouse spinal cord membranes, [D-Trp7]sendide potently displaced [3H] labeled SP binding with a Ki value of 0.023 +/- 0.007 nM, which was approximately 140 and 9400 times more potent than that of unlabeled SP and CP-96,345, respectively. These findings suggest that [D-Trp7]sendide interacts selectively with the NK1 receptor in the mouse spinal cord as assayed by the receptor binding and SP-induced behavioural tests.
Sakurada
T
T
Department of Pharmacology, Tohoku College of Pharmacy, Sendai, Japan.
Yogo
H
H
Manome
Y
Y
Tan-No
K
K
Sakurada
S
S
Yamada
A
A
Kisara
K
K
Ohba
M
M
D000595:Amino Acid Sequence; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015320:Tachykinins / Q000037:antagonists & inhibitors / Q000494:pharmacology
D000700:Analgesics; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; C090191:tryptophyl(7)-sendide; D013373:Substance P