Astrocytes harbour functional receptors to many neurotransmitters, including substance P (SP), an undecapeptide belonging to the tachykinin family of peptide transmitters. SP activates malignant glial cells to induce cytokine release and proliferation, both responses being relevant for tumour progression. In tumours developed in nude mice transplanted subcutaneously (s.c.) to U373 MG human glioma cells, the presence of SP was observed at immunohistochemistry. Although the administration of exogenous SP did not significantly affect the size or development of U373 MG xenograft, a role of SP in supporting glioma progression in vivo was highlighted by the tumour growth inhibition induced by highly specific and selective human tachykinin NK1 receptor antagonists (MEN 11467 and MEN 11149). The anti-tumour activity of MEN 11467 was observed both with s.c. or intravenous treatments and was partially reverted by the concomitant administration of exogenous SP. Doxorubicin did not show any activity in controlling U373 MG growth in this in vivo model. A novel therapeutic approach to treat malignant gliomas with tachykinin NK1 receptor antagonists is suggested by these findings.

01 Jan 1998·European Journal of PharmacologyQ3 · MEDICINE

Pharmacology of the peptidomimetic, MEN 11149, a new potent, selective and orally effective tachykinin NK1 receptor antagonist

Q3 · MEDICINE

Article

Author: Rosa Terracciano ; Giuseppe Lopez ; Massimo Parlani ; Mara Astolfi ; Christopher I Fincham ; Stefano Manzini ; Rocco Cirillo ; Bruno Conte

In this study we investigated the pharmacological properties of MEN 11149, 2-(2-naphthyl)-1-N-[(1R,2S)-2-N-[1(H)indol-3-ylcarbonyl]aminocy clohexanecarbonyl]-1-[N'-methyl-N'-(4-methylphenylacetyl)]di aminoethane, a novel partially retro-inverse pseudo peptide antagonist of tachykinin NK1 receptors. MEN 11149 potently inhibits the binding of [3H]substance P to tachykinin NK1 sites in IM9 cells (pKi = 8.5 +/- 0.1). The compound is highly specific for the human tachykinin NK1 receptors, since it has negligible effects (pKi < 6) on the binding of specific ligands to tachykinin NK2, NK3 receptors and a battery of central and peripheral receptors or ion channels. The tachykinin NK1 receptor antagonism of MEN 11149 appears to be insurmountable since, in saturation binding experiments, both K(D) and Bmax are significantly affected by incubation with the compound (1-30 nM). In isolated guinea-pig ileum, MEN 11149 (0.1-100 nM) shifts to the right in a non-parallel way the substance P methyl ester-induced cumulative concentration-response curve with progressive inhibition of the maximal response (pK(B) = 9.6 +/- 0.1). When tested for reversibility at 5 nM in the same preparation, the compound displays a slow dissociation rate compared to the fast dissociation rate with FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-methy l-N-phenylmethyl-L-3-(2-naphthyl)alaninamide) at 5 nM. In the same preparation, MEN 11149 (10 microM) did not affect the cumulative concentration-response curve to acetylcholine. In vivo, MEN 11149 dose dependently antagonizes [Sar9,Met(O2)11]substance P-induced bronchoconstriction in anaesthetized guinea-pigs (ID50 = 83 +/- 31 nmol/kg i.v.). The duration of the effect exceeds 3 h. MEN 11149 does not affect the bronchoconstriction induced by neurokinin A. The compound dose dependently inhibits [Sar9,Met(O2)11]substance P-induced plasma protein extravasation in guinea-pig bronchi whether administered intravenously (ID50 = 0.22 +/- 0.02 micromol/kg) or orally (ID50 = 0.97 +/- 0.21 micromol/kg). These results demonstrate that MEN 11149 is a potent, highly selective and orally effective insurmountable antagonist of tachykinin NK1 receptors with a long duration of action.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Discovery	IT	A. Menarini Industrie Farmaceutiche Riunite SRL	-
Inflammation	Discovery	IT	A. Menarini Industrie Farmaceutiche Riunite SRL	-

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