Synthesis and biological evaluation of novel NK-1 tachykinin receptor antagonists: the use of cycloalkyl amino acids as a template.
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
A
Chemistry Department, Menarini Ricerche Sud, Roma, Italy.
Bonelli
F
F
Centini
F
F
Fincham
C I
CI
Potier
E
E
Monteagudo
E
E
Lombardi
P
P
Arcamone
F
F
Goso
C
C
Manzini
S
S
D000596:Amino Acids; D002942:Circular Dichroism; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis
D000596:Amino Acids; D007211:Indoles; D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides; D013373:Substance P