Pharmacological characterisation of NK sub(1) receptor antagonist, [D-Trp super(7)]sendide, on behaviour elicited by substance P in the mouse

An analogue of sendide, [D-Trp super(7)]sendide, was newly synthetized and evaluated as a putative NK sub(1) receptor antagonist in a mouse behavioural test. Effects of [D-Trp super(7)]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 NK sub(1) receptors, [D-Trp super(7)]sendide inhibited the behavioural response to this tachykinin in a dose-dependent manner. The behavioural response elicited by other NK sub(1) receptor agonists, septide and physalaemin, was reduced significantly by a small dose of [D-Trp super(7)]sendide. Large doses of [D-Trp super(7)]sendide were needed to reduce the characteristic behaviour of NK A, an NK sub(2) agonist, NK B, an NK sub(3) agonist and eledoisin, an NK sub(2)/NK sub(3) agonist. The duration of the antagonistic effect of [D-Trp super(7)]sendide was relatively longer. In a [ super(3)H]labeled SP binding assay using mouse spinal cord membranes, [D-Trp super(7)]sendide potently displaced [ super(3)H] labeled SP binding with a Ki value of 0.023 plus or minus 0.007 nM, which was approximately 140 and 9400 times more potent than that of unlabeled SP and CP-96,345, respectively. The findings suggest that [D-Trp super(7)]sendide interacts selectively with the NK sub(1) receptor in the mouse spinal cord as assayed by the receptor binding and SP-induced behavioural tests.