Synthesis and biological evaluation of novel NK‐1 tachykinin receptor antagonists: The use of cycloalkyl amino acids as a template

Sisto, Alessandro; Bonelli, Fabio; Centini, F.; Fincham, Christopher I.; Potier, Edoardo; Monteagudo, Edith; Lombardi, Paolo; Arcamone, Federico; Goso, Cristina; Manzini, Stefano; Giolitti, Alessandro; Maggi, Carlo Alberto; Venanzi, Mariano; Pispisa, B.

doi:10.1002/bip.360360413

Cited by 14 publications

(13 citation statements)

References 22 publications

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“…An experimental study by Sisto et al identified a parallel arrangement. 15 This was corroborated by a linear correlation between the photochemical parameters (extinction coefficient and fluorescence quantum yield) of the ligands and their biological activities, where the parallel stacked configuration responsible for higher extinction coefficients and lower fluorescence quantum yields corresponded to higher activities. Horwell et al generated structure-activity relationships (SARs) for a series of peptidic NK1R antagonists and found descriptors such as the surface area, log P, log P 2 , the total dipole moment, and the number of methyl groups to be predictive for binding affinity.…”

Section: Introductionmentioning

confidence: 72%

Multiple-Conformation and Protonation-State Representation in 4D-QSAR: The Neurokinin-1 Receptor System

et al. 2000

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Using a 4D-QSAR approach (software Quasar) allowing for multiple-conformation, orientation, and protonation-state ligand representation as well as for the simulation of local induced-fit phenomena, we have validated a family of receptor surrogates for the neurokinin-1 (NK-1) receptor system. The evolution was based on a population of 500 receptor models and simulated during 40 000 crossover steps, corresponding to 80 generations. It yielded a cross-validated r(2) of 0.887 for the 50 ligands of the training set (represented by a total of 218 conformers and protomers) and a predictive r(2) of 0.834 for the 15 ligands of the test set (70 conformers and protomers). A series of five "scramble tests" (with an average predictive r(2) of -0.438) demonstrates the sensitivity of the surrogate toward the biological data, for which it should establish a QSAR. On the basis of this model, the activities of 12 new compounds - four of which have been synthesized and tested in the meantime - are predicted. For most of the NK-1 antagonists, the genetic algorithm selected a single entity - out of the up to 12 conformers or protomers - to preferably bind to the receptor surrogate. Moreover, the evolution converged at an identical protonation scheme for all NK-1 antagonists. This indicates that 4D-QSAR techniques may, indeed, reduce the bias associated with the choice of the bioactive conformation as each ligand molecule can be represented by an ensemble of conformations, orientations, and protonation states.

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Section: Introductionmentioning

confidence: 72%

Multiple-Conformation and Protonation-State Representation in 4D-QSAR: The Neurokinin-1 Receptor System

et al. 2000

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“…SR 140333 (14) was supplied by Dr. Edmonds-Alt (Senofi Recherche). Men 10930 (15) was provided by Dr. Manzini (A. Menarini Pharmaceuticals). CP 96345 (16), CP 99994 (17), RP 67580 (18), and CGP 49823 (19) were a gift of Dr. Schwartz (University of Copenhagen).…”

Section: Ligands and Reagents-monoiodinatedmentioning

confidence: 99%

A Mutation Changes Ligand Selectivity and Transmembrane Signaling Preference of the Neurokinin-1 Receptor

Riitano

Werge²,

Costa

1997

Journal of Biological Chemistry

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We studied the biochemical properties of a genetically engineered neurokinin-1 receptor (NK 1 R) in which two residues lying on the extracellular edge of the fourth transmembrane domain were replaced by equivalently located elements of the neurokinin-2 receptor (G166C, Y167F NK 1 R mutant). The mutation produced two effects. The first is enhancement of the apparent binding affinity for heterologous tachykinins (substance K and neurokinin B) and for N-or C-terminal modified analogues of substance P, but not for substance P itself, its full-length analogues, and several peptide and nonpeptide antagonists. Only two antagonists, as exceptions, were found to exhibit a diminished affinity for the mutant receptor. The second effect is a shift in NK 1 R preference for distinct G protein-mediated signaling pathways. NK 1 R-mediated phosphoinositide hydrolysis was enhanced both in transiently and permanently transfected cells, while stimulation of cAMP accumulation did not change in transient expression experiments and was reduced in permanently expressing cells.The effect of the mutation on ligand affinity was not related to any obvious structural commonality, nor to the selectivity for different neurokinin receptors or the agonistic/antagonistic nature of the ligand. However, all ligands responding to the mutation appear to share the ability to induce phosphoinositide signaling more efficiently than cAMP responses when binding to NK 1 R. We suggest that the mutation shifts the internal equilibria of different functional forms of NK 1 R. A theoretical analysis according to a multistate allosteric model suggests that the link between binding and biological changes can result from altered stability constants of substates in the conformational space of the receptor.Tachykinins, as several other families of neuropeptides, display a bipartite distribution of topochemical information on their sequence. The C-terminal half of the molecule is a consensus motif tightly conserved among all known hormones from mammalian and nonmammalian species (1, 2) and, conceivably, constitutes a default conditional element to establish binding affinity for any kind of tachykinin receptor subtype (3,4). The N-terminal part is instead variable even among the three mammalian tachykinin types, and it is believed to contribute interactions establishing selectivity for specific receptor subtypes (3, 4). The interesting question is whether a similar partition in the molecule of the receptor corresponds to such a sharp division between variant and invariant elements in the molecule of the peptide and, if so, to what relative extent do selective and nonselective interactions contribute to the final binding affinity of each peptide hormone and receptor system.We focused on two amino acids marking the junction between the fourth putative transmembrane domain (TMD) 1 and the second extracellular loop of tachykinin receptors. Replacement of these two residues in the substance P receptor (neurokinin-1 receptor (NK 1 R)) with those located at equivalent pos...

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“…All compounds were synthesized as reported previously (4). Analytically pure chemicals were purchased from Novabiochem, Aldrich, Fluka and Janssen and used as such.…”

Section: Methodsmentioning

confidence: 99%

“…Analytically pure chemicals were purchased from Novabiochem, Aldrich, Fluka and Janssen and used as such. The determination of binding affinity at the NK 1 receptor was performed by assessing the displacement of [ 3 H]SP binding to human lymphoblastoma IM9 cells, as described previously (4). The results were expressed in terms of p K i , i.e.…”

Section: Methodsmentioning

confidence: 99%

“…Abbreviations: The concept of designing bioactive pseudopeptides or nonpeptides requires knowledge of the biologically active conformation and the three‐dimensional topography of the pharmacophore elements in the compound. The efforts of tailoring bioactive materials by molecular modeling, often restrained by experimental data, have thus increased greatly in recent years (1–4).…”

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confidence: 99%

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A spectroscopic and molecular modeling study on novel pseudopeptides exhibiting biological activity

Pispisa¹,

Stella²,

Venanzi³

et al. 1999

The Journal of Peptide Research

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A series of pseudopeptides, containing two fluorophores, such as naphthalene (N) and indole (I), and exhibiting interesting biological activity as tachykinin receptor antagonists, were investigated by electronic absorption, CD and steady-state fluorescence experiments. In polar solvents (e.g. methanol), bioactivity is coupled with a stacked, charge-separated complex between I and N, the amount of which depends on the stereochemical features and conformational mobility of the central scaffold in the molecules examined. This agrees with the idea that dipolar charged, spatially close, aromatic moieties are important topochemical elements in the mechanism of action of these receptor antagonists. Molecular mechanics calculations allowed us to build up hypothetical, low-energy conformations of a few representative pseudopeptides, whose structural features are consistent with the experimental findings.

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Synthesis and biological evaluation of novel NK‐1 tachykinin receptor antagonists: The use of cycloalkyl amino acids as a template

Cited by 14 publications

References 22 publications

Multiple-Conformation and Protonation-State Representation in 4D-QSAR: The Neurokinin-1 Receptor System

Multiple-Conformation and Protonation-State Representation in 4D-QSAR: The Neurokinin-1 Receptor System

A Mutation Changes Ligand Selectivity and Transmembrane Signaling Preference of the Neurokinin-1 Receptor

A spectroscopic and molecular modeling study on novel pseudopeptides exhibiting biological activity

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