The Structural Determinants for α1-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives

Several studies confirmed the reciprocal interactions between adrenergic and serotoninergic systems and the influence of these phenomena on the pathogenesis of anxiety. Hence, searching for chemical agents with a multifunctional pharmacodynamic profile may bring highly effective therapy for CNS disorders. This study presents a deep structural insight into the hydantoin-arylpiperazine group and their serotonin/α-adrenergic activity. The newly synthesized compounds were tested in the radioligand binding assay and the intrinsic activity was evaluated for the selected derivatives. The computer-aided SAR analysis enabled us to answer questions about the influence of particular structural fragments on selective vs. multifunctional activity. As a result of the performed investigations, there were two leading structures: (a) compound 12 with multifunctional adrenergic-serotonin activity, which is a promising candidate to be an effective anxiolytic agent; (b) compound 14 with high α1A/α1D affinity and selectivity towards α1B, which is recommended due to the elimination of probable cardiotoxic effect. The structural conclusions of this work provide significant support for future lead optimization in order to achieve the desired pharmacodynamic profile in searching for new CNS-modulating agents.

Assessing the affinity of oxazolidinedione/hydantoin derivatives for the human 5HT1A/2A receptor through homology modeling and docking studies

A flexible docking of a series of heteroaryl compounds to the binding site of a model of human 5-HT1A/2A receptor was exercised using GLIDE docking methods. The resultant docking scores were used to correlate the in vivo affinity data. The GLIDE docking algorithm when used with a homology model of 5HT1A/2A was based on β2- adrenergic receptor template. The influence of structure and hydrophobic properties of aryl moiety on binding affinities was discussed and a model for ligand binding in the hydrophobic part of the binding site was proposed.

Molecular rearrangement of pyrazino[2,3-c]quinolin-5(6H)-ones during their reaction with isocyanic acid

A new tetrahydropyrazino[2,3-c]quinolin-5(6H)-ones were prepared from 3-chloroquinoline-2,4(1H,3H)-diones and ethylene diamine. In their reaction with HNCO, an unprecedented molecular rearrangement produced new types of hydantoin derivatives. All prepared compounds are characterized using their 1H, 13C, and 15N NMR spectra and the results of the X-ray analysis are also presented. A proposed mechanism of rearrangement is discussed in this essay.

Rational Engineering of the Substrate Specificity of a Thermostable D-Hydantoinase (Dihydropyrimidinase)

D-hydantoinases catalyze an enantioselective opening of 5- and 6-membered cyclic structures and therefore can be used for the production of optically pure precursors for biomedical applications. The thermostable D-hydantoinase from Geobacillus stearothermophilus ATCC 31783 is a manganese-dependent enzyme and exhibits low activity towards bulky hydantoin derivatives. Homology modeling with a known 3D structure (PDB code: 1K1D) allowed us to identify the amino acids to be mutated at the substrate binding site and in its immediate vicinity to modulate the substrate specificity. Both single and double substituted mutants were generated by site-directed mutagenesis at appropriate sites located inside and outside of the stereochemistry gate loops (SGL) involved in the substrate binding. Substrate specificity and kinetic constant data demonstrate that the replacement of Phe159 and Trp287 with alanine leads to an increase in the enzyme activity towards D,L-5-benzyl and D,L-5-indolylmethyl hydantoins. The length of the side chain and the hydrophobicity of substrates are essential parameters to consider when designing the substrate binding pocket for bulky hydantoins. Our data highlight that D-hydantoinase is the authentic dihydropyrimidinase involved in the pyrimidine reductive catabolic pathway in moderate thermophiles.