Biomedical subjects
Publications and source records attributed to Ae Nim Pae.
Synthesis of novel substituted tetrahydropyrans with adjacent exo-methylene groups at the C3 and C4 positions via Prins-type cyclization has been described.
We have prepared and evaluated the antibacterial activities of a series of substituted methylenepiperidinyl and methylenepyrrolidinyl oxazolidinones against several gram-positive strains including the resistant strains of Staphyloccus and Enterococcus, such as MRSA, CRSA, MSSA and VRE. Some of them showed comparable or superior in vitro activities (MIC) to vancomycin.
QSAR studies for piperazinylalkylisoxazole analogues were conducted by hologram QSAR (HQSAR) and comparative molecular field analysis (CoMFA) to explain the binding affinities of 264 ligands acting on dopamine D(3) receptor. The HQSAR was assessed by r(2) value of 0.917 and cross validated q(2) value of 0.841. In the CoMFA, r(2) is 0.919 and cross validated q(2) is 0.727. The results provide the tools for predicting the affinity of related compounds and guiding the design of new ligands.
In vitro metabolic stability of dopamine D(3)/D(4) receptor antagonists and identification of their metabolites by high-performance liquid chromatography (HPLC) coupled with ion-trap mass spectrometry (ITMS) were assessed in rat liver microsomes. The compounds were divided into three cassette groups for rapid quantitative analysis of multiple drugs and simultaneous detection of their metabolites. The samples from incubation with rat liver microsomes were pooled into designed cassette groups and analyzed by HPLC/electrospray ITMS in full-scan mode. The metabolic stability of the drugs was determined by comparing their signals after incubation for 0 and for 30min. The metabolic stability of the examined dopamine receptor antagonists was in the range of 9.9-84.4%. In addition, the present cassette analysis allowed the simultaneous detection of metabolites formed during the same incubation without having to reanalyze the samples. The metabolites were first characterized by nominal mass measurement of the corresponding protonated molecules. Subsequent multistage tandem mass spectrometry on the ion-trap instrument allowed characterization of the structure of the detected metabolites. N,O-dealkylation and ring hydroxylation reactions were identified as major metabolic reactions in piperazinylalkylisoxazole derivatives. These results suggested that the present approach is useful for the rapid evaluation of metabolic stability and structural characterization of metabolites within a short period in new drug discovery.
1-(2-ethoxy-phenyl)-4-[3-(3-thiophen-2-yl-isoxazolin-5-yl)-propyl]-piperazine (KCH-1110), has a high affinity for human dopamine D3 (hD3) receptor (Ki=1.28 nM) with about 90-fold selectivity over the human dopamine D2L (hD2L) receptor. Antipsychotic or antidopaminergic activity of KCH-1110 was investigated in the models for the positive symptoms of schizophrenia, apomorphine-induced climbing and cocaine-induced hyperlocomotion, in mice. Intraperitoneal (i.p.) or oral (p.o.) administration of KCH-1110 potently inhibited the apomorphine-induced cage climbing without any rotarod ataxia in mice. Cocaine-induced hyperactivity was also antagonised by KCH-1110. In addition, KCH-1110 attenuated the hypothermia induced by a selective dopamine D3 agonist, 7-OH-DPAT in mice. KCH-1110 did not induce catalepsy in mice, but at much higher doses only a slight catalepsy response was shown. Although high doses of KCH-1110 significantly enhanced serum prolactin secretion in rats, low dose of KCH-1110 did not increase prolactin levels in rats. The present studies, therefore, suggest that KCH-1110 is a potent and relatively selective dopamine D3 receptor antagonist with antipsychotic actions.
[reaction: see text] Intramolecular Prins-type reactions of compounds having both functionalities of homoallyl alcohol and acetal moiety are described. The intramolecular Prins cyclizations were performed using indium trichloride in chloroform or 25% aqueous THF. Both 9-oxabicyclo[3.3.1]nonane and 3,9-dioxabicyclo[3.3.1]nonane compounds were successfully obtained in moderate yields.
A piperazinylbutylisoxazole libary was designed, synthesized and screened for the binding affinities to dopamine D2, D3, and D4 receptors. Several ligands were identified to possess high binding affinity and selectivity for the D3 and D4 receptors over the D2 receptor. Compounds 6s and 6t showed K(i) values of 2.6 nM and 3.9 nM for the D3 receptor with 46- and 50-fold selectivity over the D2 receptor, respectively.
A data set of 130 diverse compounds containing both central nervous system (CNS) and non-CNS drugs was used to generate a renal clearance model using a classical Volsurf approach. Percentage renal clearance data was used as a biological input. The score plots obtained from principal component analysis and partial least-squares (PLS) analysis clearly separated high-clearance compounds from low-clearance compounds. PLS models were used to predict the renal clearance of the data set. Categorical statistical methods such as SIMCA and recursive partitioning techniques were used for classifying the compounds into low- and high-clearance categories. PLS coefficient plots, Volsurf descriptor profiles, 3D Grid maps, and RP decision trees were used to explain the important descriptors separating low and high renal clearance compounds. For comparative purposes, topological descriptors such as Molconn-Z were also examined. All the models were validated by an external test set of 20 compounds. These models can be used as efficient tools in the classification and prediction of the renal clearance of unknown compounds, the knowledge of which is helpful in understanding their bioavailability behavior.