Nuclear estrogen receptors co-activation mechanisms.

Estrogens play very important role in opening the transcription event, which is a final step of activation of the first order mediators as receptors or channels in the cell wall by information coming from the outside of the cell. For the long time the exact step by step mechanism of cellular transfer of information to the cell nuclei was not known. Currently many new informations are available. Very important seems the step of phosphorylation and therefore desensitization of the target proteins. All peptide kinases, especially serine and threonine, like protein kinases A and C, RAS and MAP kinases, cycline kinases are potential or confirmed biological targets. Except them elements of the transcription complexes like p160.SRC-1, histon acetyltransferase and histon deacetylase, CBP/p300, TRAP/DRIP, NSD1, PPARγ/PGC-1, NCOR1, SMRT, REA were also found useful. Finally estrogens are able to activate other receptors, namely aryl hydrocarbon receptors (AhR) and estrogen receptor related proteins (ERR). It is well known that many types of cancer are related to the direct or indirect excessive activation of nuclear estrogen receptors, therefore their inhibition could be crucial in many estrogen-related cancers. Understanding the interactions in such complexes would help in developing new and better multi-target cures and finding new ligands with better pharmacological and pharmacokinetic properties.

Molecular structure of ionotropic glutamate receptors.

L-glutamate is the major excitatory neurotransmitter in the central nervous system (CNS). Although just a few glutamate receptor ligands have turned out to be clinically useful, primarily because of unfavorable psychotropic side effects, the glutamate system remains an attractive molecular target in the treatment of epilepsy, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's chorea), schizophrenia, ischemia, pain, alcoholism and mood disorders. Knowledge about the structure of ionotropic glutamate receptors (iGluRs) at atomic resolution is vital for the determination of their physiological and pathological importance and, thus, for drug design. Recently, tremendous progress has been made in structure elucidation and understanding of the functioning of iGluRs. The data about general topology and modular composition of iGluRs as well as numerous crystal structures of ligand binding domains of many iGluR subtypes has been supplemented with the first molecular models of the whole receptor protein, followed by the first crystal structures of N-terminal domains and finally by the first crystal structure of the whole tetrameric iGluR. This review summarizes experimental and computational efforts to determine iGluR molecular architecture and focus on the above listed achievements of the last years. In particular, the aspects of iGluR structure which are important for drug design, like the molecular characterstics of the ligand binding sites, are depicted in detail.

Synthesis and pharmacological activity of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine. Part 1. Synthesis and pharmacological activity of chain derivatives of 1-aryl-2-iminoimidazolidine containing urea moiety.

The synthesis and physicochemical properties of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine are presented. Isomeric 1-(1-arylimidazolidine-2-ylidene)-3-arylureas (series A) and 1-aryl-2-imine-3-arylaminocarbonylimidazolidines (series B) were obtained after the condensation reaction of 1-aryl-2-iminoimidazolidines and arylisocyanates. 1-Aryl-2-iminoimidazolidines were synthesised in a two-step reaction from the respective anilines. The molecular structure of 1-(1-phenylimidazolidine-2-ylidene)-3-(4-chlorophenyl)urea (A2) has been determined by X-ray crystallography. The representatives of both investigated series were evaluated in behavioural animal tests. They exhibited significant, especially analgesic, activity on the animal central nervous system (CNS). They displayed substantial effect on the serotonine and catecholamine neurotransmission as well, at very low toxicity (LD(50) over 2000 mg kg(-1) i.p.). In the binding affinity tests they exhibited moderate affinity (on the micromolar level) toward opioid (mu) and serotonine (5HT(2)) receptors. The derivatives of series A had moderate affinity toward benzodiazepine (BZD) receptor as well. Distinctive differences observed in their activity spectra can be connected with the presence of particular structural features such as relative orientation of the two aromatic rings and the carbonyl moiety.

Electron ionisation induced fragmentation of ethyl 5(1H)-oxo- and 7(1H)-oxo-1-aryl-2,3-dihydroimidazo[1,2-a]-pyrimidine-6-carboxylates: evidence for an unusually regioselective rearrangement of M(+*) ions.

The 70-eV electron ionisation (EI) mass spectra of the title compounds show clear differences between the 5-oxo and 7-oxo isomers due to regioselective fragmentations involving the ester function. Exceptionally abundant metastable peaks due to molecular ions fragmenting to [M -CO2](+.) were observed exclusively for the 7-oxo isomers, suggesting that the sufficiently long-lived molecular ions undergo a slow rearrangement preceding this fragmentation reaction. The results are contrasted to the available literature data on the ester group fragmentations involving the loss of CO2 and the EI mass spectrometry of pyrimidone beta-oxo esters. A reaction mechanism is proposed for the elimination of CO2 following ethyl group migration to the pyrimidone carbonyl oxygen.

Synthesis and biological action of 3,4-disubstituted 5-arylsulphonylamine-1,2,4-triazoles.

The synthesis of 3,4-disubstituted 5-arylsulphonylamine-1,2,4-triazoles is described. The antimicrobial activities of the compounds were investigated as well as their acute toxicity.

Synthesis of new derivatives of 1-alkyl-2-aryl-1H-2,3-dihydroimidazo[1,2-a]pyrimidin-5-one active in CNS. Part 2. Synthesis and results of preliminary pharmacological screening of 7-(substituted)amino-1-alkyl-2-aryl-1H-2,3-dihydroimidazo[1,2-a]pyrimid in-5- ones.

Synthesis of new 7-(substituted)amino-1-alkyl-2-aryl-1H-2,3-dihydroimidazo[1,2-a]py rimidin-5- ones bearing the 4-arylpiperazin-1-yl moiety connected by ethyl or acetoyl two-carbonyl chain extension was described. The arylpiperazinyl moiety was introduced by alkylation or acylation with corresponding halogeno-derivatives. Preliminary pharmacological screening showed the 7-(substituted)-amino derivatives of the system investigated to exhibit the CNS activity lesser than that of the 7-amino derivatives and to have no effect on the serotonin neurotransmission pathway.

Synthesis and CNS activity of new 1-alkyl-2-aryl-7-hydroxy-5(1H)oxo-imidazo[1,2-a]pyrymidines.

Cyclocondensation of 1,5-disubstituted 2-aminoimidazolines with diethyl malonate in the presence of sodium methanolate leading to imidazol[1,2-alpyrimidine-5,7-dion system is presented. Prevailing of 7-hydroxy-5(1H)oxo form between three possible tautomers is discussed based on spectral data. CNS activity of nine compounds is evaluated.

Synthesis and some central pharmacological properties of new 5(1H)oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylic esters.

Six new 5(1H)oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylic ethyl esters bearing an aromatic substituent in position 1 or 2 were obtained. Pharmacological studies on the central action of these derivatives were carried out on mice and rats. The highest activity showed compounds 1 and 2 which produced analgesic effects in mice.

Synthesis and some central pharmacological properties of new derivatives of 2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylic acid.

Twenty one derivatives of 2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylic acid (6 n-butyl amides and 15 free acids) bearing the aromatic ring in position 1 or 2 were obtained. They were synthesized by aminolysis or hydrolysis of respective ethyl esters. Pharmacological studies on the central action of eight compounds 1, 2, 4, 5, 7, 8, 9 and 10 were carried out on mice and rats. The most active compounds, producing sedation and hypothermia, and 1, 2 and 5. The compounds decreased amphetamine-induced hyperactivity. Besides, compound 2 exerted analgesic effect in mice.