Synthesis and biological activity of NK1 tachykinin antagonists not containing D-residues

Poulos, Constantine; Antoniou, Maria A.; Patacchini, Riccardo; Maggi, C.A.; Rovero, Paolo

doi:10.1016/0143-4179(94)90093-0

Cited by 3 publications

(2 citation statements)

References 7 publications

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“…Poulos et al . (16–18) were the first group to demonstrate that hexapeptidyl analogs of SP modified on both the C‐terminal side‐chain and the carboxamide group could be antagonists without the presence of a β‐turn type II′ constraint. We found (unpublished results) that their most potent antagonist Orn‐Phe‐Phe‐Gly‐Leu‐Asp(OBzl)‐OBzl (17) antagonized both [Pro 9 ]SP‐ and [pGlu 6 , Pro 9 ]SP (6–11) (septide)‐induced IPs formation in CHO cells transfected with the hNK‐1 receptor with p K B values of 7.40 ± 0.10 and 7.66 ± 0.03, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to these two families, Poulos et al . (16,17) showed that hexapeptides of SP modified simply on both the carboxamide and the side‐chain of the C‐terminal methionine may have antagonist activity, the analog Orn‐Phe‐Phe‐Gly‐Leu‐Asp (OBzl)‐OBzl being the most potent. The presence of two benzene rings is not, however, a prerequisite for antagonist activity in this peptide analog.…”

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confidence: 99%

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Analogs of Substance P modified at the C‐terminus which are both agonist and antagonist of the NK‐1 receptor depending on the second messenger pathway

Sachon¹,

Girault-Lagrange²,

Chassaing³

et al. 2002

The Journal of Peptide Research

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The initial goal of this study was to analyze, using photolabeling, the interactions between Substance P and its tachykinin NK-1 receptor. Therefore, the photoreactive amino acid para-benzoyl-phenylalanine (pBzl)Phe was incorporated into the Substance P sequence from position 4 to 11 leading to Bapa0[(pBzl)Phex]SP analogs. Biotinyl sulfone-5-aminopentanoic acid (Bapa) was introduced in order to purify the covalent complex. These photoreactive SP analogs were first assayed for their affinity for the two binding sites associated with the NK-1 receptor, as well as for their potency in activating the phospholipase C and adenylate cyclase pathways. All analogs photoreactive from position 4 to 11 have moderate to high affinity for the two NK-1 receptor-binding sites, except for the analog modified at position 7. This affinity could be correlated to their potency to activate the phospholipase C and adenylate cyclase pathways, except for the analog photoreactive at position 11. Bapa0[(pBzl)Phe11]SP was found to be an agonist in the phospholipase C pathway and an antagonist in the adenylate cyclase pathway, other analogs modified at position 11 were therefore analyzed. Among these, Bapa0[Pro9, (pBzl)Hcy(O2)11]SP is a partial agonist, whereas Bapa0[Hcy(ethylaminodansyl)11]SP is a full agonist in the phospholipase C pathway, the two analogs being antagonist in the adenylate cyclase pathway. These results show that analogs of SP can be simultaneously agonist at one binding site and antagonist at the other binding site associated with the NK-1 receptor.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Analogs of Substance P modified at the C‐terminus which are both agonist and antagonist of the NK‐1 receptor depending on the second messenger pathway

Sachon¹,

Girault-Lagrange²,

Chassaing³

et al. 2002

The Journal of Peptide Research

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GR 73,632 and [Glu(OBzl)11]substance P are selective agonists for the septide-sensitive tachykinin NK1 receptor in the rat urinary bladder

et al. 1995

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Conformational Analysis of the C-Terminal Gly-Leu-Met-NH2 Tripeptide of Substance P Bound to the NK-1 Receptor

Sagan¹,

Quancard²,

Lequin³

et al. 2005

Chemistry & Biology

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We examined the effect of simultaneously incorporating proline or proline-amino acid chimeras in positions 9, 10, and/or 11 of substance P, on the affinity for the two NK-1 binding sites and on second-messenger activation. Because these 3-substituted prolines constrain not only the (phi,psi) values of the peptide backbone, but also the chi space of the amino acid side chain, we were able to gather data on the structural requirements for high-affinity binding to the NK-1 receptor. We were able to confirm that this C-terminal component is crucial and that it should adopt an extended conformation close to a polyproline II structure when bound to the receptor. The partial additivity of these constraints, more specifically, for the NK-1M site, suggests that the peptide backbone flexibility around the hinge-point residue Gly9 is essential to subtly position crucial side chains.

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Synthesis and biological activity of NK1 tachykinin antagonists not containing D-residues

Cited by 3 publications

References 7 publications

Analogs of Substance P modified at the C‐terminus which are both agonist and antagonist of the NK‐1 receptor depending on the second messenger pathway

Analogs of Substance P modified at the C‐terminus which are both agonist and antagonist of the NK‐1 receptor depending on the second messenger pathway

GR 73,632 and [Glu(OBzl)11]substance P are selective agonists for the septide-sensitive tachykinin NK1 receptor in the rat urinary bladder

Conformational Analysis of the C-Terminal Gly-Leu-Met-NH2 Tripeptide of Substance P Bound to the NK-1 Receptor

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