Highly selective agonists for substance P receptor subtypes.

Abstract

The existence of a third tachykinin receptor (SP‐N) in the mammalian nervous system was demonstrated by development of highly selective agonists. Systematic N‐methylation of individual peptide bonds in the C‐terminal hexapeptide of substance P gave rise to agonists which specifically act on different receptor subtypes. The most selective analog of this series, succinyl‐[Asp6,Me‐Phe8]SP6‐11, elicits half‐maximal contraction of the guinea pig ileum through the neuronal SP‐N receptor at a concentration of 0.5 nM. At least 60,000‐fold higher concentrations of this peptide are required to stimulate the other two tachykinin receptors (SP‐P and SP‐E). The action of selective SP‐N agonists in the guinea pig ileum is antagonized by opioid peptides, suggesting a functional counteraction between opiate and SP‐N receptors. These results indicate that the tachykinin receptors are distinct entities which may mediate different physiological functions.

Molecular characterisation, expression and localisation of human neurokinin‐3 receptor

“…into nuclei of Xenopus laevis oocytes. Neurokinins increased current amplitude (data not shown) with the relative rank-order of potency: NKB>NKA>SP which is consistent with the actions of an NK-3 receptor [2,11,12,28]. Half-maximally effective concentrations of NKB and NKA were 4 nM and 40 nM, respectively.…”

“…NK-3 receptors also mediate increased phosphoinositide hydrolysis in guinea pig ileum and neonatal rat spinal cord [2,8]. In addition, NK-3 receptors depolarize guinea pig myenteric neurons to augment release of acetyleholine [9][10][11], stimulate contraction of the rat portal vein [12] and modulate both serotinergieand ¢holinergic-dependent behavioural responses in mouse and rat [13,14]. Despite these observations indicating an important physiological role controlling transmitter release and vascular tone in some species, NK-3 receptors have not been identified in human tisCorrespondeneeaddreas: ( sues.…”

Novel selective agonists and antagonists confirm neurokinin NK1 receptors in guinea‐pig vas deferens

“…The established NK3 selective agonist, senktide, was inactive (1O nM-32 pM). This agonist is inactive in several other NK1 preparations (Laufer et al, 1986a,b;Wormser et al, 1986). The novel NK2 agonist GR64349 had very little activity over the concentration-range l0nM-l, p, but at concentrations greater than 10pM, potentiation of the twitch response was seen to give a very steep log concentration response curve in this region and approached the magnitude of effect of several other agonists.…”

Comparative behavioural profile of centrally administered tachykinin NK1, NK2 and NK3 receptor agonists in the guinea‐pig

“…route in guinea-pigs. The agonists used were septide ([pGlu6,, Wormser et al, 1986), [Sar9,Met(02)"]SP (Regoli et al, 1988) and [ProlSP (Lavielle et al, 1986) for the NKI tachykinin receptor, [Lys5, MeLeu9, Nle'INKA(4-10) (Chassaing et al, 1991) for the NK2 tachykinin receptor and senktide (succinyl-[Asp6,MePhe8]SP(6 -1), Laufer et al, 1986) for the NK3 tachykinin receptor. It has been demonstrated in mice that behavioural responses induced by intrathecal or i.c.v.…”