Biomedical subjects

R Y Ji

Publications and source records attributed to R Y Ji.

At least 37 records · Page 2Linked to original sources

PubMed1997

Structure-activity relationship of channel binding affinity of quaternary ammonium ions.

AIM: To explore the structure-activity relationship of quaternary ammonium (QA) ions at the external binding site of K+ channel. METHODS: InsightII and MOPAC 6.0 molecular modeling package were used to calculate the free energy of hydration (delta Ghydration), the energy of the highest occupied orbital (EHOMO), and the energy of the lowest unoccupied orbital (ELUMO) for each QA ion, respectively. The partial least square method was used to analyze the relationship between the binding free energy and these descriptive parameters. RESULTS: Generally, the higher the ELUMO of a QA ion was, the weaker its solvation was and accordingly the stronger binding affinity. For a QA ion larger than tetraethylammonium (TEA), its large size was unfavorable to its channel binding affinity. CONCLUSION: The binding affinity of all QA ions correlated well with delta Ghydration and ELUMO.

Binding Sites↗

PubMed1996

Molecular modeling of interactions between tetrahydroprotoberberines and dopamine receptors.

AIM: To build up the structure models of dopamine receptors, then combined with the receptor models, to investigate the action mechanism of tetrahydroprotoberberines (THPB) on dopamine receptors at the molecular level. METHODS: Using the three-dimensional structure of bacteriorhodopsin as a template, we have constructed dopamine D1 and D2 receptor models on computer. l-Stepholidine was selected as the leading compound of THPB and docked into D1 and D2 receptor active sites. RESULTS: After manual adjustment and energy minimization, the ligand-receptor interaction models were achieved. Based on these models, the possible action mechanism of THPB on dopamine receptors was suggested that the protonated N atom of THPB form electrostatic interaction and hydrogen-bonding interaction with residue Asp in TM3 of the receptor, the two substituents in D ring of THPB form hydrogen-bonding interactions with two Ser residues in TM5 of the receptor, and the aryl groups form pi-pi interactions with some aryl residues of the receptor around ligand. CONCLUSION: Our ligand-receptor interaction models should be helpful for rational design of more potent drugs.

Amino Acid Sequence↗

PubMed1996

Molecular modeling of mu opioid receptor and its interaction with ohmefentanyl.

AIM: To build up the structure model of mu opioid receptor, then combined with the receptor model, to investigate the action mechanism of ohmefentanyl on the receptor. METHODS: Using the three-dimensional structure of bacteriorhodopsin as a template, we constructed mu opioid receptor model on computer. Ohmefentanyl was then docked into the supposed receptor binding sites. RESULTS: A good ligand-receptor interaction model was achieved. The possible binding sites were found to be Asp147 and His319. The protonated N atom of ohmefentanyl form potent electrostatic and hydrogen-bonding interactions with residue Asp147 of the receptor, the O atom of the carbonyl group form weak electrostatic and hydrogen-bonding interactions with residue His319, and the two phenyl groups form pi-pi interactions with some aryl residues of the receptor around ligand. CONCLUSION: The ligand-receptor interaction model should be helpful for rational design of novel analgesic.

Amino Acid Sequence↗

PubMed1995

Stereoisomers of N-[1-hydroxy-(2-phenylethyl)-3-methyl-4-piperidyl]- N-phenylpropanamide: synthesis, stereochemistry, analgesic activity, and opioid receptor binding characteristics.

N-[1-(2-Hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide (ohmefentanyl,1) is an extremely potent analgesic agent with high affinity and selectivity for opioid mu receptors. There are three chiral carbons in 1, so eight optically active isomers are possible. Respective reaction of optically active 3-methyl-N-phenyl-4 -piperidinamines (5a-d) with (R)- or (S)-styrene oxide produced eight optically active intermediates which were subsequently converted to eight optically active isomers of 1 (1a-h). The absolute configurations of 1a-h were determined by X-ray analysis of (3R,4S,2'R)-(-)-cis-1a and (3R,4R,2'S)-(-)-trans-1g. The analgesic activity (mice, ip, hot plate) revealed their extreme stereodifferences; the ED50 values of (3R,4S,2'R)-(-)-cis-1a and (3R,4S,2'S)-(+)-cis-1b, which are the most potent isomers among eight isomers, were 0.004 65 (2990 times that of morphine) and 0.001 06 mg/kg (13 100 times that of morphine), respectively, while the corresponding antipodes 1d,c were the least potent compounds among the eight isomers. In agreement with pharmacological results, both 1a,b also had the highest receptor affinity and selectivity for the opioid mu receptor. The ratio of K(i)(DPDPE)&K(i)(DAMGO) was 22 800 for 1a and 22 500 for 1b. All isomers except 1c,d strongly inhibited the electrically evoked smooth muscle contraction of GPI and MVD but not that of RVD, and the inhibitory effects could be reversed by naloxone, which indicated that these compounds were potent mu agonists in GPI and MVD. There was a good linear correlation between the analgesic potencies (ED50) and the receptor affinities (K(i)(DAMGO)) or inhibitory effects (IC50) to GPI and MVD. These results suggested that the analgesic effects of ohmefentanyl are mediated by interaction between the agents and opioid mu receptors in the central nervous system and the 3R,4S configuration at the piperidine 3- and 4-carbon atoms and the S configuration at the phenylethyl 2-carbon atom are beneficial for analgesic potency and inhibitory effects in GPI and MVD and the same for an S or R configuration at the phenylethyl 2-carbon atom besides the 3R,4S configuration for receptor mu affinity and selectivity.

Analgesics↗

PubMed1995

QSAR of 3-methylfentanyl derivatives studied with neural networks method.

AIM: To use neural networks, which simulate the functions of living nervous systems, in QSAR studies; METHODS: Using the back-propagation neural networks program devised by us, combining with partial least squares (PLS) method, we studied the relationships of quantum chemical indices and analgesic activities of 25 3-methylfentanyl derivatives; RESULTS: Through learning process, a good QSAR model was established, and the activities of these compounds were predicted; the correlation between the activities and quantum chemical indices: the net charge of the atom N1, the net charge of the atom O16, the torsional angle of atoms C10-C9-N8-C4, the interatomic distance between atom C7 and the center of phenyl plane C9-14 (PhA), is quite well-matched. Based on these results, an interactive pattern between 3-methylfentanyl derivatives and opioid receptors was suggested; CONCLUSION: Not only are the results of neural networks superior to those of PLS method but they also provide accurate predictions of the activity of the compounds and also combine the PLS method with neural networks.

Analgesics↗

PubMed1994

3D-QSAR study on ether and ester analogs of artemisinin with comparative molecular field analysis.

Comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (3D-QSAR) paradigm, was used to study the correlations between the physicochemical properties and the in vitro activities of a series of ether and ester analogs of artemisinin. Four alignment models were used in the CoMFA investigation. The correlations derived from CoMFA analysis with the four alignments proved all to have good predictive values. The steric field predictive model of alignment B is accordant with the experimental results of Avery M A, et al: J Med Chem 1993; 36: 4264-75. The electrostatic field predictive results of alignments A, B, and C are consistent with our previous result of quantum chemical calculation. The highest rcross2 of alignment D, indicated that the side chain of -C6-O2-O1-C10-O3-C7-O4-C12-O5- and atom C16 are important groups of artemisinin analogs for antimalarial activity.

Antimalarials↗

PubMed1993

[Stereoisomers of 3-methylfentanyl: synthesis, absolute configuration and analgesic activity].

Fractional crystallization of fumarate salt and oxalate salt of the mixture of cis- and trans-N-(3-methyl-4-piperidyl)-aniline (6) gave pure cis-6 x fumarate salt and trans-6 x oxalate salt respectively. Four optically pure 6 were obtained via resolution of cis-6 and trans-6 with D- and L-tartaric acid. Respective reaction of the optically pure 6 with phenylethyl bromide following propionylation gave optically active 3-methylfentanyl (2). The absolute configuration was confirmed: cis-(+)-2 as (3R,4S), cis-(-)-2 as (3S,4R), trans-(+)-2 as (3S,4S), trans-(-)-2 as (3R,4R). Pharmacological results showed that the configuration of two chiral centers in 2 was very important for analgesic potency. The median effective dose (ED50) of cis-(+)-2, which is the most potent among the four isomers, was found to be 0.00767 mg/kg (in mice, ip., hot plate) with 2600 times as potent as morphine while 119 and 1.5 times as potent as cis-(-)-2 and cis-(+/-)-2 respectively. The potency ratio between trans-(+)-2 and morphine was calculated as 450:1, while that between trans-(+)-2 and trans-(-)-2 as 4:1.

Analgesics↗

PubMed1991

[Synthesis of (+/-)-edulinine analogues].

The natural product, edulinine (I), possesses analgesic, anaesthetic and anticonvulsant activities on the central nervous system. In this paper we report that a series of edulinine analogues IV, V were synthesized and screened in mice according to methods of Topliss and Austel quantitative drug design. In preliminary pharmacological tests a number of synthesized compounds showed central depressant activities stronger than edulinine.

Analgesics↗

PubMed1989

[Synthesis of pyrido [1,2-a] pyrimidinone series of compounds, potential agents on the nervous system].

In an effort to modify the structure of edulinine so to seek compounds exhibiting higher potency toward inhibition of central nervous system, we designed and synthesized several analogous compounds: 2-methoxy-3-(3-methyl-2-butenyl)-4-oxo-4 H-pyrido [1,2-a] pyrimidine (IV), 3-methoxy-3-(3-methyl-2-butenyl)-2-oxo-2H-pyrido[1,2-a]pyrimidine (V), 2-methoxy-3-(2,3-dihydroxy-3-methyl-1-butyl)-4-oxo-4H-pyrido[1,2-a] pyrimidine (VI), and 4-methoxy-3-(2,3-dihydroxy-3-methyl-1-butyl)-2-oxo-2H-pyrido[1,2-a] pyrimidine (VII). Animal experiments revealed that compound (IV) has anticonvulsant activity, compounds (V) and (VI) have far lower activity than compound (IV).

Anticonvulsants↗

PubMed1987

A study on configuration-activity relationship of diamminedichloroplatinum (II) by the pseudopotential valence electron-only ab initio calculation method.

We investigated the cis- and trans-isomers of Pt(NH3)2Cl2 and [Pt(NH3)2]2+ using a quantum chemical non-empirical calculation method, the pseudopotential valence electron-only ab initio method. The electronic structure and electrostatic potential counter maps were in turn determined through the wave functions so obtained. There was a sharp difference between the dipole moments of the cis- and trans-isomers. The electrostatic counter maps of the isomers also had remarkably different features. Based on the interaction between the platinum (II) coordination compound and the base pairs of nucleic acid, the difference in antitumour activity of the isomeric compounds was discussed. It is pointed out that the key factor for antitumour activity is that the platinum (II) coordination compound must be mutually complementary with the target acceptor in both configuration and bonding activity. This mutual-complementary requirement includes a bonding ability of the platinum complex with two negative centers in DNA, so as to form an intrastrand crosslink with two neighbouring guanines.

Antineoplastic Agents↗

PubMed1986