Pharmacology of MEN 11467: a potent new selective and orally- effective peptidomimetic tachykinin NK1 receptor antagonist

Cirillo, R; Astolfi, M.; Conte, Bruno; Lopez, G.; Parlani, Massimo; Sacco, G. Di; Terracciano, Rosa; Fincham, Christopher I.; Sisto, Alessandro; Evangelista, Stefano; Maggi, C.A.; Manzini, Stefano

doi:10.1054/npep.2001.0855

Cited by 11 publications

(12 citation statements)

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“…-(2-naphthyl)alanyl}diaminocyclohexane; MW = 600.8) (Cirillo et al, 1998a;Palma et al, 1999b) and MEN 11149 (2-(2-naphthyl)-1-N-{(1R,2S)-2-N-[1(H)indol-3-yl-carbonyl]aminocyclohexane carbonyl}-1-[N′-methyl-N′-(4-methylphenylacetyl)]diaminoethane; MW = 600) (Cirillo et al, 1998b), were synthesized at the Chemistry Department of Menarini Ricerche, Pomezia, Italy (Figure 1). For the purposes of this study, these antagonists were solubilized in dimethyl sulphoxide (DMSO) and diluted in saline containing 6% Tween-80.…”

Section: Drugsmentioning

confidence: 99%

“…All reagents were purchased from Gibco Laboratories (Grand Island, NY, USA). SP, a selective agonist of NK 1 tachykinin receptor in guinea pig (Cirillo et al, 1998a(Cirillo et al, , 1998b.…”

Section: Cell Culturementioning

confidence: 99%

“…A role of SP in U373 MG in vivo growth was highlighted by the anti-tumour activity obtained with SP receptor antagonists. The pseudopeptide, MEN 11467, which possesses a high affinity for the human tachykinin NK 1 receptor but does not bind the murine NK 1 receptor (Cirillo et al, 1998a), was used to block NK 1 receptors expressed in U373 MG cells. As shown in Figure 3, s.c. treatment with MEN 11467 (1 µmol kg -1 twice weekly for 2 weeks) resulted in a temporary growth arrest of the U373 MG xenograft that lasted for about 10 days until the last MEN 11467 administration (TVI% = 56).…”

Section: Effect Of Tachykinin Nk 1 Receptor Antagonists On U373 Mg Xementioning

confidence: 99%

mentioning

confidence: 95%

“…(Cirillo et al, 1998a;Palma et al, 1999b). On the contrary they had virtually no affinity (K i values ≥ 10 000 nM) for rat or murine tachykinin NK 1 receptors (Cirillo et al, 1998a(Cirillo et al, , 1998b. Receptor blockade by both antagonists resulted in a powerful and complete inhibition of functional U373 MG responses induced by SP, such as accumulation of the second messenger inositol monophosphate or interleukin-6 release (Palma et al, 1999a(Palma et al, , 1999b.…”

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Anti-tumour activity of tachykinin NK1 receptor antagonists on human glioma U373 MG xenograft

et al. 2000

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Malignant astrocytomas or glioblastomas represent the most common type of primary brain tumour in adults (Salcman and Kaplan, 1986;Hochberg and Pruitt, 1987). High-grade malignant gliomas are inevitably lethal neoplasms and the median survival of patients treated with standard cytoreductive surgery and postoperative radiotherapy is in the range of 1 year. Likewise chemotherapy is of limited effectiveness in the treatment of these tumours and other therapeutic approaches must be explored. Glioblastomas are sensitive to several hormones and growth factors. The presence of receptors for epidermal growth factor, platelet-derived growth factor, insulin-like growth factor-I/II as well as for glucocorticoid, androstenedione and progesterone in malignant gliomas, has been described (Shapiro et al, 1995). Recently, neurotransmitters/neuropeptides have also been found to regulate astrocytoma growth (Sharif, 1998).Substance P (SP), an undecapeptide of the tachykinin family of neuropeptides, is released both in the central and peripheral nervous systems, playing a well established role in neuronal transmission, vasodilatation and motor responses (Maggi et al, 1993). Tachykinins exert their actions through activation of G-protein coupled receptors, labelled NK 1 , NK 2 , NK 3 ; SP is the preferential endogenous ligand for the tachykinin NK 1 receptor (Maggi et al, 1993;Otsuka and Toshioka, 1993). In various astrocytic/glial brain tumour-derived cell lines, the presence of tachykinin NK 1 receptor strictly correlates with the effect of SP and/or NKA in increasing DNA synthesis and cellular proliferation Sharif et al, 1996;Palma et al, 1999a). In addition, SP can control many other glial responses such as taurine release, secretion of various cytokines (e.g. interleukin (IL)-6, IL-8, transforming growth factor-β, leukaemia inhibitory factor, granulocyte-macrophage colony stimulating factor) which are thought to be relevant for glioma progression (Gitter et al, 1994;Palma et al, 1995;Palma and Manzini, 1998). In a large number of these studies, the human astrocytoma grade III U373 MG cell line, which expresses a high level of functional tachykinin NK 1 receptor (Lee et al, 1992;Palma et al, 1999b) but not tachykinin NK 2 or NK 3 receptors (Heuillet et al, 1993), were used.The role of SP in glioma activities may be ascribed to a pathological use of normal signal transduction pathways occurring in reactive astrocytes. In fact, SP activates phospholipase C and stimulates the release of IL-6 and prostaglandin E 2 from human fetal astrocytes in culture (Palma et al, 1997), and there is evidence for an up-regulation of this receptor by reactive proliferating astrocytes after transection of the optic nerve (Mantyh et al, 1989). Moreover, SP-immunoreactive astrocytes have been observed in multiple sclerosis plaques (Kostyk et al, 1989) and in the forebrains of human infants (Michel et al, 1986). Interestingly, the involvement of tachykinin NK 1 receptor and SP in glioma progression was not only supported by the functional in vitro stud...

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Section: Drugsmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

Section: Effect Of Tachykinin Nk 1 Receptor Antagonists On U373 Mg Xementioning

confidence: 99%

mentioning

confidence: 95%

mentioning

confidence: 99%

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Anti-tumour activity of tachykinin NK1 receptor antagonists on human glioma U373 MG xenograft

et al. 2000

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Tachykinin NK1 Receptor Antagonists

Patacchini

Maggi

2004

Handbook of Experimental Pharmacology

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Involvement of endogenous tachykinins and CGRP in the motor responses produced by capsaicin in the guinea-pig common bile duct

Patacchini

Barthó

Giorgio

et al. 1999

Naunyn-Schmiedeberg's Arch Pharmacol

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In functional experiments, we have investigated the effect exerted by neurotransmitters released from capsaicin-sensitive primary afferent nerve terminals in the isolated guinea-pig common bile duct. In resting preparations, capsaicin (0.1 microM) produced a quick contraction (45.1+/-4% of KCl 80mM) which was abolished by either atropine (1 microM) or tetrodotoxin (0.5 microM). The tachykinin receptor-selective antagonists GR 82334 (NK1 receptor-selective; 3 microM), MEN 11420 (NK2 receptor-selective; 1 microM) and SR 142801 (NK3 receptor-selective; 0.1 microM) administered separately failed to reduce the capsaicin-evoked contraction, whereas any combination of the three antagonists was effective: GR 82334 plus MEN 11420, 36+/-7% reduction; GR 82334 plus SR 142801, 48+/-4% reduction; MEN 11420 plus SR 142801, 55+/-3% reduction; GR 82334 plus MEN 11420 plus SR 142801, 57+/-5% reduction. Neither the CGRP1 receptor antagonist h-CGRP (8-37) (1.5 microM) nor the P2X purinoceptor antagonist PPADS (50 microM) affected the contractile response to capsaicin. The effect of capsaicin (0.1 microM) was abolished by pretreatment with capsaicin itself (10 microM for 15 min). Human calcitonin gene-related peptide (h-CGRP; 0.1 microM) mimicked the effect of capsaicin on resting preparations (contractile response =28% of KCl 80 mM). In preparations precontracted with a submaximal concentration of KCl (24 mM), and in the presence of atropine (1 microM), GR 82334 (3 microM) and MEN 11420 (3 microM), capsaicin (1 microM) produced a tetrodotoxin-insensitive long-lasting relaxation (45+/-3% reduction of tone, at 4min from administration), which was unaffected by the nitric oxide (NO) synthase inhibitor, L-NOARG (100 microM). h-CGRP (10-50 nM) produced a similar sustained relaxation of precontracted preparations (59+/-4% reduction of tone). h-CGRP (8-37) (1.5 microM) almost completely reversed the relaxations produced by both capsaicin and h-CGRP. Application of electrical field stimulation (EFS: trains of stimuli of 10Hz; 0.25ms pulse width; supramaximal voltage; for 60s) to precontracted preparations produced a sustained, tetrodotoxin (1 microM)-sensitive relaxation (32+/-4% reduction of tone). L-NOARG (100 microM) greatly reduced (69+/-5% inhibition) the EFS-elicited relaxation. A complete reversal of the relaxant response to EFS into a contraction was obtained by administering L-NOARG to preparations in which a functional blockade of capsaicin-sensitive primary afferent neurons had been achieved by incubating the tissue with capsaicin (10 microM) for 15 min. At immunohistochemistry, tachykinin- and CGRP-immunoreactivities (TK-IR/CGRP-IR) were detected in varicose nerve fibers throughout the common bile duct, while TK-IR cell bodies were observed in the terminal portion (ampulla) only. In vivo pretreatment with capsaicin (50 mg/kg; 6-7 days before) decreased the number of CGRP-IR nerves, whereas the TK-IR neural network was apparently unchanged. In conclusion, our data provide functional evidence for the presence of capsaicin-sensiti...

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Pharmacology of MEN 11467: a potent new selective and orally- effective peptidomimetic tachykinin NK1 receptor antagonist

Cited by 11 publications

References 28 publications

Anti-tumour activity of tachykinin NK1 receptor antagonists on human glioma U373 MG xenograft

Anti-tumour activity of tachykinin NK1 receptor antagonists on human glioma U373 MG xenograft

Tachykinin NK1 Receptor Antagonists

Involvement of endogenous tachykinins and CGRP in the motor responses produced by capsaicin in the guinea-pig common bile duct

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