In the course of a program aimed at synthesizing novel, potent NK-1 tachykinin receptor antagonists, we developed upon a bioactive model by comparing the low energy structures of a series of peptide and nonpeptide Substance P antagonists. The comparison was based on the superimposition of the aromatic rings, assuming that the rest of the molecule behaves predominantly as a template to arrange the key aromatic groups in the right spatial position. A series of 2-aminocyclohexane carboxylic acid analogues were then selected as the best templates for reproducing the postulated bioactive structure, leading to several pseudo-peptides with interesting biological activity. According to the molecular modeling, these compounds exhibit a neat parallel facing of the indolyl and naphthyl groups at about 3 A distance. Ultraviolet absorption and steady state fluorescence measurements support this conclusion, showing a linear correlation between the spectral properties and the binding affinity of these analogues. Stacking of the indole ring with naphthalene gives rise to a complex characterized by a well-defined molar extinction coefficient. Consistently, steady state and lifetime fluorescence measurements suggest that the quenching process is ascribable to ground-state interactions between the chromophores. Implications of the pi stacking propensity of aromatic groups in the biological activity of the compounds examined are briefly discussed.

Sisto, A., Bonelli, F., Centini, F., Fincham, C., Potier, E., Monteagudo, E., et al. (1995). Synthesis and Biological Evaluation of Novel NK-1 Tachykinin Receptor Antagonists: the Use of cycloalkyl amino acids as a template. BIOPOLYMERS, 36, 511-524.

Synthesis and Biological Evaluation of Novel NK-1 Tachykinin Receptor Antagonists: the Use of cycloalkyl amino acids as a template

VENANZI, MARIANO;PISPISA, BASILIO
1995

Abstract

In the course of a program aimed at synthesizing novel, potent NK-1 tachykinin receptor antagonists, we developed upon a bioactive model by comparing the low energy structures of a series of peptide and nonpeptide Substance P antagonists. The comparison was based on the superimposition of the aromatic rings, assuming that the rest of the molecule behaves predominantly as a template to arrange the key aromatic groups in the right spatial position. A series of 2-aminocyclohexane carboxylic acid analogues were then selected as the best templates for reproducing the postulated bioactive structure, leading to several pseudo-peptides with interesting biological activity. According to the molecular modeling, these compounds exhibit a neat parallel facing of the indolyl and naphthyl groups at about 3 A distance. Ultraviolet absorption and steady state fluorescence measurements support this conclusion, showing a linear correlation between the spectral properties and the binding affinity of these analogues. Stacking of the indole ring with naphthalene gives rise to a complex characterized by a well-defined molar extinction coefficient. Consistently, steady state and lifetime fluorescence measurements suggest that the quenching process is ascribable to ground-state interactions between the chromophores. Implications of the pi stacking propensity of aromatic groups in the biological activity of the compounds examined are briefly discussed.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore CHIM/02 - Chimica Fisica
English
Sisto, A., Bonelli, F., Centini, F., Fincham, C., Potier, E., Monteagudo, E., et al. (1995). Synthesis and Biological Evaluation of Novel NK-1 Tachykinin Receptor Antagonists: the Use of cycloalkyl amino acids as a template. BIOPOLYMERS, 36, 511-524.
Sisto, A; Bonelli, F; Centini, F; Fincham, C; Potier, E; Monteagudo, E; Lomabardi, P; Arcamone, F; Goso, C; Manzini, S; Giolitti, A; Maggi, C; Venanzi, M; Pispisa, B
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/130686
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