1,4-Diacylpiperazine-2-(S)-[(N-aminoalkyl)carboxamides] as novel, potent substance P receptor antagonists.

doi:10.1016/S0960-894X(01)80747-2

Bioorganic & Medicinal Chemistry Letters

Volume 3, Issue 12, December 1993, Pages 2707-2712

https://doi.org/10.1016/S0960-894X(01)80747-2 Get rights and content

Abstract

A series of N,N′-diacylpiperazine-2-carboxamides are shown to be antagonists of the NK-1 (Substance P) receptor. Elaboration of the C2 sidechain with aminoalkyl groups leads to two series of potent antagonists, one containing simple dialkylamino groups and the second featuring 2-methoxybenzylamino derivatives with divergent SARs with respect to substitution at the C2 amide bond.

A series of N,N′-diacylpiperazine-2-carboxamides are shown to be potent, selective antagonists of the NK-1 (Substance P) receptor.

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The tachykinin NK₁ receptor couples with G-proteins to determine its biological effects in target cells. Several G-proteins both sensitive (Go, Gi) and insensitive (Gq, G11) to pertussis toxin can mediate the action of NK₁ receptors. Moreover, several second messanger signalling systems (elevation of intracellular calcium, stimulation of phosphoinositol turnover, arachidonic acid mobilization, cAMP accumulation) have to be activated following NK₁ receptor signalling. Also a direct modulation of certain ion channels at membrane level has been proposed. The NK₁ receptor undergoes prompt and significant tachyphylaxis upon exposure to the agonist: this has been shown to be linked with receptor internalization which also occurs physiologically when the NK₁ receptor is stimulated by endogenous tachykinins.
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The immunosuppressive cyclic undecapeptide, cyclosporin A, inhibited the binding of [¹²⁵I]substance P to tachykinin NK₁ receptors expressed by human IM-9 lymphoblastoid cells, U-373 MG human astrocytoma cells and guinea pig lung parenchyma with IC₅₀ values of 425 ± 58, 783 ± 180, and 784 ± 163 nM respectively. The dihydro derivative of cyclosporin A (dihydro-cyclosporin A) was an equally effective inhibitor, but the O-acetylated derivative (cyclosporin A-OAc) was 3–4-fold less potent. The cyclosporin compounds also inhibited [¹²⁵I]neurokinin A binding to human NK₂ receptors with potencies slightly less than at NK₁ sites. In contrast, they were 8–20-fold less effective inhibitors of [¹²⁵I]MePhe⁷-neurokinin B binding to guinea pig NK₃ receptors (p < 0.001). Thus, the cyclosporin A compounds showed selectivity for NK₁ and NK₂ receptors The structure-activity pattern for the effects of cyclosporin A compounds at tachykinin receptors differs from the pattern previously described for their immunosuppressive activity. All three compounds inhibited substance P induced interleukin-6 (IL-6) secretion from U-373 MG astrocytoma cells with potencies similar to their NK₁ receptor binding affinities. In addition, cyclosporin A blocked substance P induced phosphatidylinositol (PI) turnover in U-373 MG cells without blocking the corresponding response to histamine. This novel pharmacological profile of the cyclosporin A compounds as NK₁ receptor antagonists does not appear to correlate with other known in vitro cyclosporin A functions.

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1,4-Diacylpiperazine-2-(S)-[(N-aminoalkyl)carboxamides] as novel, potent substance P receptor antagonists.

Abstract

Life Sci.

Annu. Rev. Med.

Science

Biochem. Biophys. Res. Commun.

Neuroscience

J. Physiol. (London)

J. Med. Chem.

Proc. Nat. Acad. Sci. U.S.A.

BioMed. Chem. Lett.

J. Physiol., (London)

J. Auton. Pharmacol.