piperidines and azacyclonol

We recently reported 2,4,5-trimethylpyridin-3-ol with C(6)-azacyclonol, whose code name is BJ-1207, showing a promising anticancer activity by inhibiting NOX-derived ROS in A549 human lung cancer cells. The present study was focused on structural modification of the azacyclonol moiety of BJ-1207 to find a compound with better anticancer activity. Ten new compounds (3A-3J) were prepared and evaluated their inhibitory actions against proliferation of eighteen cancer cell lines as a primary screening. Among the ten derivatives of BJ-1207, the effects of compounds 3A and 3J on DU145 and PC-3, androgen-refractory cancer cell lines (ARPC), were greater than the parent compound, and compound 3A showed better activity than 3J. Antitumor activity of compound 3A was also observed in DU145-xenografted chorioallantoic membrane (CAM) tumor model. In addition, the ligand-based target prediction and molecular docking study using DeepZema® server showed compound 3A was a ligand to M3 muscarinic acetylcholine receptor (M3R) which is overexpressed in ARPC. Carbachol, a muscarinic receptor agonist, concentration dependently increased proliferation of DU145 in the absence of serum, and it also activated NADPH oxidase (NOX). The carbachol-induced proliferation and NOX activity was significantly blocked by compounds 3A in a concentration-dependent manner. This finding might become a new milestone in the development of pyridinol-based anti-cancer agents against ARPC.

Topics: Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Male; Molecular Structure; Piperidines; Prostatic Neoplasms; Pyridines; Receptor, Muscarinic M3; Structure-Activity Relationship; Tumor Cells, Cultured

To further characterize cytochrome P450 (CYP) and P-glycoprotein (Pgp) expression in monolayers of the Caco-2 cell clone TC7, a cell culture model of the human intestinal epithelium. To study the interplay between CYP3A and Pgp as barriers to intestinal drug absorption in TC7 cells using terfenadine and its metabolites as substrates.. mRNA expression of eight CYPs and Pgp was investigated in TC7 and parental Caco-2 (Caco-2p) cell monolayers using RT-PCR. The CYP3A kinetics was determined in microsomes from both cell lines. The transport, metabolism and efflux of terfenadine and its metabolites were investigated in TC7 monolayers.. Both TC7 and Caco-2p cells expressed mRNA for Pgp and several important CYPs. However, mRNA for CYP3A4 was detectable anly from TC7 cells. The relative affinity of CYP3A for terfenadine metabolism in the two cell lines was comparable, but the maximum reaction rate in the TC7 cells was 8-fold higher. The rate of transport of terfenadine and its metabolites hydroxy-terfenadine (HO-T) and azacyclonol across TC7 monolayers was 7.1-, 3.5- and 2.1-fold higher, respectively, in the basolateral to apical direction than it was in the apical to basolateral (AP-BL) direction. Inhibition studies indicated that the efflux was mediated by Pgp. Ketoconazole increased the AP-BL transport terfenadine dramatically by inhibiting both terfenadine metabolism and Pgp efflux.. Cell culture models such as TC7 provide qualitative information on drug interactions involving intestinal CYP3A and Pgp.

Topics: Anti-Anxiety Agents; Antifungal Agents; Aryl Hydrocarbon Hydroxylases; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Caco-2 Cells; Calcium Channel Blockers; Catalytic Domain; Cell Polarity; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Digoxin; Enzyme Inhibitors; Epithelial Cells; Gene Expression; Histamine H1 Antagonists; Humans; Hydroxylation; Intestinal Mucosa; Intestines; Ketoconazole; Kinetics; Oligonucleotide Probes; Oxidoreductases, N-Demethylating; Piperidines; RNA, Messenger; Terfenadine; Tritium; Verapamil

In this work, a method for the determination of azacyclonol, a primary metabolite of terfenadine, in human serum is described. Sample preparation is carried out by liquid-liquid extraction under basic conditions. For an efficient clean up, the analytes are back-extracted into diluted hydrochloric acid and, after alkalinization, are once again extracted into the organic phase. No derivatisation step is performed. The samples are measured by gas chromatography-mass spectrometry with good selectivity. The limit of detection is 2 ng/ml. The coefficients of variation are 12.6% at 10 ng/ml and 6.44% at 200 ng/ml in the day-to-day control measurements.

Topics: Anti-Anxiety Agents; Gas Chromatography-Mass Spectrometry; Humans; Piperidines; Sensitivity and Specificity; Terfenadine

A stereoselective and sensitive achiral/chiral method for the determination of terfenadine acid metabolite in human plasma was developed. The metabolite was separated and quantitated using an achiral chromatographic procedure with a cyano column. The mobile phase was 1 mM sodium acetate buffer (pH 4.0) and acetonitrile (25:75% v/v) at a flow rate of 2 ml/min, at ambient temperature. The stereospecific resolution was accomplished using a chiral-AGP column and a mobile phase consisting of sodium acetate (0.01 M): methanol (98.7:1.3% v/v), and 20 mM di-n-butylamine at a flow rate of 1.2 ml/min. The column temperature was maintained at 32 degrees C. The eluent was monitored at 230 nm (excitation) and 300 nm (emission) with a cut-off filter at 270 nm. This assay was used for a pharmacokinetic study in five subjects after administration of a single dose of 60 mg of terfenadine. The t1/2 values of the two enantiomers were similar, but the AUC values of the (+)-enantiomer were 2.05-2.35 times higher than those of (-)-enantiomer.

Topics: Administration, Oral; Adult; Chromatography; Chromatography, High Pressure Liquid; Humans; Male; Piperidines; Stereoisomerism; Structure-Activity Relationship; Terfenadine

A gas chromatographic-mass spectrometric (GC-MS) method is presented for the analysis of azacyclonol (AZA), a metabolite of terfenadine in serum and urine specimens. Following an alkaline extraction, AZA and an internal standard were derivatized using heptafluorobutyric anhydride. Fourier transform infrared spectrometry suggested that two sites on the AZA molecule were derivatized. GC-MS of the extracts had a limit of quantitation (LOQ) of 1 ng/ml and linear range of 1-1000 ng/ml in urine. Four volunteers were administered a therapeutic regimen of terfenadine followed by urine and serum specimen collection(s) during the next seven days. The results indicated that following a 60-mg dose of terfenadine each 12 h for five days, (1) AZA appears in urine within 2 h, (2) urine AZA concentrations were above the LOQ 72 h following the last dose, (3) peak urine concentrations were as high as 19,000 ng/ml, and (4) mean serum concentration following the ninth dose was 59 ng/ml.

Topics: Adult; Fourier Analysis; Gas Chromatography-Mass Spectrometry; Humans; Male; Piperidines; Spectrophotometry, Infrared; Terfenadine

Topics: Blood Glucose; Carbohydrate Metabolism; Diabetes Mellitus; Glucose Tolerance Test; Hallucinations; Hospitals, Psychiatric; Inpatients; Mental Disorders; Piperidines; Placebos; Schizophrenia; Toxicology

Topics: Adolescent; Catatonia; Child; Chlorpromazine; Convulsive Therapy; Electroconvulsive Therapy; Humans; Insulin; Methotrimeprazine; Perphenazine; Piperidines; Reserpine; Schizophrenia; Toxicology

Topics: Amitriptyline; Atropine; Avoidance Learning; Chlorpromazine; Cocaine; Desipramine; Dextroamphetamine; Guanethidine; Imipramine; Iproniazid; Isocarboxazid; Methylphenidate; Parasympatholytics; Pharmacology; Piperidines; Promazine; Promethazine; Rats; Research; Scopolamine; Tetrabenazine; Trihexyphenidyl; Tyramine

Topics: Behavior, Animal; Body Temperature; Chlorpromazine; Conditioning, Classical; Hallucinogens; Lysergic Acid Diethylamide; Mescaline; Mice; Pharmacology; Piperidines; Psychotropic Drugs; Rats; Reflex; Research; Reserpine

Topics: Blood-Brain Barrier; Brain; Chlordiazepoxide; Chlorpromazine; Cyproheptadine; Dopamine; Electricity; Fluorometry; Norepinephrine; Pharmacology; Piperidines; Rats; Research; Shock; Tetrabenazine; Thioridazine; Tranquilizing Agents

Topics: Chlormezanone; Chromatography; Colorimetry; Crystallography; Forensic Medicine; Hydroxyzine; Meprobamate; Phenothiazines; Piperidines; Reserpine

Topics: Brain; Brain Chemistry; Chlorpromazine; Electricity; Electroshock; Pharmacology; Piperidines; Rats; Research; Serotonin; Shock; Tetrabenazine

The effect of some centrally-active and other drugs on the transmission of single nerve impulses through the isolated superior cervical ganglion preparation of the rabbit has been studied by recording both preganglionic and postganglionic action potentials. Block of conduction in the axon could be distinguished from block of the synaptic mechanism. The drugs did not appear to exert any one characteristic form of blocking action. A continuous spectrum of drug action linked an agent such as meprobamate which acted predominantly on the synapse to benactyzine which acted mainly by blocking axonal conduction. The drugs have been divided into three groups. Group I: hexamethonium, meprobamate, paraldehyde, amylobarbitone, methylpentynol and azacyclonal; these acted relatively selectively at the ganglion. Group II: N714C (the cis-isomer of chlorprothixene), prochlorperazine, methylpentynol carbamate, pipradrol, promethazine, perphenazine and procaine; the action of these drugs on the ganglion could be accounted for entirely in terms of their axonal depressant action. Group III: chlorprothixene, promazine, N720 (dihydrochlorprothixene), chlorpromazine, hydroxyzine and benactyzine; these drugs also blocked axonal conduction but in addition they appeared to exert a "facilitating" action at the ganglionic synapse. The actions of adrenaline, adrenochrome, iproniazid, ergotoxine, mescaline and lysergic acid diethylamide on transmission were also studied. The implications of the modifications of ganglionic transmission produced by these drugs is discussed.

Topics: Action Potentials; Animals; Barbiturates; Benactyzine; Chlorpromazine; Chlorprothixene; Ganglia, Autonomic; Ganglionic Blockers; Hexamethonium Compounds; Hydroxyzine; Hypnotics and Sedatives; Meprobamate; Neural Conduction; Paraldehyde; Perphenazine; Pharmacology; Piperidines; Procaine; Prochlorperazine; Promazine; Promethazine; Rabbits; Research; Superior Cervical Ganglion

Topics: Animals; Arginine Vasopressin; Creatine; Creatinine; Piperidines; Rats; Vasopressins

Topics: Amides; Analgesia; Carisoprodol; Chlorpromazine; Meprobamate; Morphine; Perphenazine; Phenothiazines; Piperidines; Prochlorperazine; Propylene Glycols; Rauwolfia; Reserpine; Thioridazine; Tranquilizing Agents

Topics: Central Nervous System Depressants; Chlorpromazine; Guinea Pigs; Humans; Hydroxyzine; Ileum; Meprobamate; Muscle Relaxants, Central; Piperidines; Prochlorperazine; Reserpine

Topics: Animals; Antineoplastic Agents; Blood; Carcinoma, Ehrlich Tumor; DNA; DNA, Neoplasm; Mice; Neoplasms; Neoplasms, Experimental; Piperidines; Prochlorperazine; Rabbits; Research; Reserpine; RNA; RNA, Neoplasm; Sarcoma 180

Topics: Animals; Behavior, Animal; Brain; Catecholamines; Chlordiazepoxide; Chlorpromazine; Electricity; Norepinephrine; Piperidines; Rats; Research; Stress, Physiological

Topics: Acetone; Animals; Blood Glucose; Epinephrine; Glucagon; Glucose Tolerance Test; Hypoglycemic Agents; Lagomorpha; Pharmacology; Piperidines; Rabbits; Research

Topics: Adenine Nucleotides; Adenosine Triphosphate; Benactyzine; Brain; Chlordiazepoxide; Coenzymes; Hydroxyzine; Meprobamate; Metabolism; Pharmacology; Phenethylamines; Phosphates; Piperidines; Rats; Research; Tranquilizing Agents

Topics: Amides; Amitriptyline; Antidepressive Agents; Benactyzine; Chemical Phenomena; Chemistry; Chlordiazepoxide; Desipramine; Diazepam; Haloperidol; Humans; Hydroxyzine; Hypnotics and Sedatives; Imipramine; Isocarboxazid; Meprobamate; Methylphenidate; Monoamine Oxidase Inhibitors; Nervous System; Nialamide; Pharmacology; Phenelzine; Piperidines; Tranquilizing Agents; Tranylcypromine; Tryptamines

Topics: Antipyretics; Biphenyl Compounds; Body Temperature; Lysergic Acid Diethylamide; Methanol; Piperidines; Salts

Topics: Animals; Bemegride; Carbachol; Epinephrine; Glutethimide; Hyperoxia; Inert Gas Narcosis; Methamphetamine; Nitrogen; Oxygen; Pentylenetetrazole; Phenacetin; Physostigmine; Piperidines; Rats; Scopolamine

Topics: Amphetamine; Chlorpromazine; Dibucaine; Diethylpropion; Dihydroxyphenylalanine; Dopamine; Ephedrine; Epinephrine; Hydrazines; Imipramine; Iproniazid; Mephentermine; Methamphetamine; Methylphenidate; Movement; Nialamide; Phenelzine; Phenethylamines; Phenmetrazine; Phenylhydrazines; Piperidines; Reserpine; Tranylcypromine; Tryptophan; Tyramine

Topics: Animals; Electroencephalography; Piperidines; Porifera; Porphyrias

Topics: Electroconvulsive Therapy; Humans; Mental Disorders; Piperidines; Psychosurgery; Psychotherapy

Topics: Convulsive Therapy; Electricity; Electroconvulsive Therapy; Electroshock; Hallucinations; Humans; Piperidines; Psychopharmacology

Topics: Chronic Disease; Hallucinations; Humans; Mental Disorders; Piperidines; Psychopharmacology; Syndrome

Topics: Hallucinations; Humans; Piperidines; Schizophrenia

Topics: Piperidines; Salts; Schizophrenia

Topics: Cardiovascular System; Epinephrine; Humans; Piperidines

Topics: Humans; Piperidines; Schizophrenia

Topics: Humans; Medical Records; Piperidines; Psychoses, Alcoholic; Psychotic Disorders; Schizophrenia

Topics: Alcoholism; Piperidines; Salts

Topics: Bile; Keto Acids; Ketones; Phenothiazines; Piperidines

Topics: Electroconvulsive Therapy; Piperidines; Psychosurgery; Psychotherapy; Psychotic Disorders

Topics: Chlorpromazine; Convulsive Therapy; Piperidines; Reserpine; Schizophrenia; Seizures

Topics: Electroconvulsive Therapy; Mental Disorders; Piperidines; Psychosurgery; Psychotherapy

Topics: Mental Disorders; Phenothiazines; Piperidines; Promazine; Psychotic Disorders

Topics: Disease; Mental Disorders; Piperidines; Psychosurgery; Psychotic Disorders; Veterans

Topics: Humans; Intellectual Disability; Piperidines; Schizophrenia

Topics: Piperidines; Schizophrenia

Topics: Dementia; Double-Blind Method; Humans; Mental Disorders; Piperidines; Psychotic Disorders

Topics: Chlorpromazine; Lysergic Acid Diethylamide; Mental Disorders; Piperidines; Psychotic Disorders

Topics: Central Nervous System; Piperidines

Topics: Humans; Piperidines; Schizophrenia

Topics: Piperidines; Schizophrenia

Topics: Piperidines; Schizophrenia

Topics: Humans; Piperidines

Topics: Piperidines; Schizophrenia

Topics: Benzhydryl Compounds; Biomedical Research; Piperidines; Schizophrenia

Topics: Electroconvulsive Therapy; Piperidines; Psychotherapy; Psychotic Disorders

Topics: Central Nervous System; Central Nervous System Stimulants; Humans; Mental Disorders; Nervous System; Piperidines; Psychotic Disorders

Topics: Confusion; Delusions; Hallucinations; Humans; Piperidines

Topics: Piperidines; Schizophrenia; Suicide

Topics: Chlorpromazine; Lysergic Acid; Lysergic Acid Diethylamide; Mental Disorders; Piperidines; Psychotherapy; Psychotropic Drugs; Reserpine

Topics: Electroconvulsive Therapy; Mental Disorders; Piperidines; Psychotic Disorders

Topics: Delusions; Hallucinations; Humans; Piperidines

Topics: Electroconvulsive Therapy; Mental Disorders; Piperidines; Psychotherapy

Topics: Barbiturates; Lysergic Acid Diethylamide; Niacin; Nicotinic Acids; Piperidines; Reserpine; Serotonin; Serotonin Antagonists

Topics: Chlorpromazine; Piperidines; Reserpine

Topics: Mental Disorders; Piperidines; Psychosurgery; Psychotic Disorders

Topics: Piperidines; Schizophrenia

Topics: Double-Blind Method; Piperidines; Salts; Schizophrenia

Topics: Electroconvulsive Therapy; Piperidines; Psychiatry; Psychosurgery; Psychotic Disorders

Topics: Electroconvulsive Therapy; Piperidines; Psychosurgery; Psychotic Disorders

Topics: Anti-Allergic Agents; Autonomic Agents; Biphenyl Compounds; Histamine H1 Antagonists; Humans; Phenothiazines; Piperidines; Psychotic Disorders; Syndrome

Topics: Chlorpromazine; Electroconvulsive Therapy; Mental Disorders; Piperidines; Psychotic Disorders; Reserpine; Secologanin Tryptamine Alkaloids

Topics: Central Nervous System Stimulants; Family Practice; General Practice; Humans; Piperidines

Topics: Chlorpromazine; Hospitalization; Humans; Mental Disorders; Piperidines; Psychosurgery; Psychotic Disorders; Reserpine; Secologanin Tryptamine Alkaloids

Topics: Hallucinations; Humans; Piperidines; Syndrome

Topics: Humans; Piperidines; Schizophrenia

Topics: Mental Disorders; Piperidines

Topics: Humans; Mental Disorders; Piperidines

Topics: Humans; Piperidines; Psychotherapy

Topics: Humans; Mental Disorders; Piperidines; Schizophrenia

Topics: Animals; Behavior; Brain; Electroencephalography; Humans; Lysergic Acid Diethylamide; Piperidines; Spinal Cord; Urodela

Topics: Electroconvulsive Therapy; Humans; Piperidines; Psychosurgery; Psychotic Disorders

Topics: Humans; Piperidines; Schizophrenia