piperidines and tempidon

We describe herein a novel metabolic fate of the 2,2,6,6-tetramethyl-piperidine (2,2,6,6-TMPi) moiety to a ring-contracted 2,2-dimethyl pyrrolidine (2,2-DMPy) in human liver microsomal incubations. The existence of this pathway was demonstrated for three compounds (I-III) of varied structures suggesting that this may be a general biotransformation reaction for the 2,2,6,6-TMPi moiety. The 2,2-DMPy metabolites formed in incubations of the three compounds with human liver microsomes were characterized by online high performance liquid chromatography coupled to a high resolution hybrid quadrupole-time-of-flight mass spectrometer. Suggested elemental composition obtained from accurate mass measurements of the molecular ions and fragment ions of the metabolites clearly indicated the loss of a mass equivalent to C(3)H(6) from the parent 2,2,6,6-TMPi functionality. Additional accurate tandem mass spectrometry data indicated that one of the original two gem-dimethyl groups was intact in the metabolite structure. Proof of a ring-contracted 2,2-DMPy structure was obtained using (1)H-NMR experiments on a metabolite purified from liver microsomal incubations, which showed only two geminal methyl groups, instead of four in the parent compound. Two-dimensional correlation spectroscopy and decoupling experiments established aliphatic protons arranged in a pyrrolidine ring pattern. The fact that the formation of 2,2-DMPy metabolites in human liver microsomes was NADPH-dependent suggested that this novel metabolic reaction was catalyzed by the cytochrome P450 (P450) enzyme(s). Immunoinhibition studies in human liver microsomal incubations using anti-P450 monoclonal antibodies and experiments with insect cell microsomes containing individually expressed recombinant human P450 isozymes indicated that multiple P450 isozymes were capable of catalyzing this novel metabolic transformation.

Topics: Biotransformation; Catalysis; Humans; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Microsomes, Liver; Piperidines; Piperidones; Pyrrolidines; Triacetoneamine-N-Oxyl

Topics: Animals; Blood Pressure; Cyclic N-Oxides; Male; Microcirculation; Muscles; Piperidines; Piperidones; Rats; Rats, Inbred Strains; Triacetoneamine-N-Oxyl; Vasodilation

Topics: Animals; Anxiety; Behavior, Animal; Female; Humans; Male; Methaqualone; Models, Psychological; Piperidines; Piperidones; Prognosis; Rats; Rats, Inbred Strains; Triacetoneamine-N-Oxyl

The authors carried out a pharmacokynetic study on the Bulgarian preparation Tempidone in rats. They examined resorption, distribution and excretion of the preparation in urine, bile and feces of rat after venous and oral administration. The experiments were carried out on 207 white male rats of the Wistar strain, weighting from 160 to 180 gm. Blood samples were obtained at various intervals from the onset of venous administration of the preparation in a dose of 100 mg/kg of body weight. After oral administration of the dose of 125 mg/kg of body weight in addition to blood samples other samples from brain, liver, stomach and intestines (small and large) were obtained as well. Excretion of Tempidone through the bile was examined after intraperitoneal administration of 250 mg/kg of body weight. They proposed pharmakynetic models after venous and oral administration of Tempidone. The obtained results gave evaluation for the rate, with which the distribution processes in the organism of rats occurred. Pharmacologic action of Tempidone coinceded in time with the creation and support of effective plasma concentrations. The wide distribution and preservation of Tempidone in the tissues suggested that it underwent the so called tissue binding.

Topics: Absorption; Administration, Oral; Animals; Dose-Response Relationship, Drug; Injections, Intravenous; Kinetics; Male; Piperidines; Piperidones; Rats; Time Factors; Tissue Distribution; Tosyl Compounds; Triacetoneamine-N-Oxyl

The authors carried out experiments on mice DBA/2 and BDF1 with leucosis L1210 and lung carcinoma of Lewis and found that psycotropic preparations tempidone and caffeine did not manifest antitumorous effect and toxicity after the used doses and scheme of treatment. Tempidone enhanced antitumorous action of small and mean doses of cyclophosphamide in mice with leucosis L1210. In the triple combination (tempidone, caffeine and cycl phosamide) the caffeine enhanced this action of tempidone without raising toxicity in mice with leucosis L1210, but not in mice with lung carcinoma of Lewis.

Topics: Animals; Caffeine; Carcinoma; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Interactions; Drug Synergism; Drug Therapy, Combination; Female; Leukemia L1210; Liver Neoplasms; Male; Mice; Mice, Inbred DBA; Mice, Inbred Strains; Neoplasm Transplantation; Neoplasms, Experimental; Piperidines; Piperidones; Psychotropic Drugs; Tosyl Compounds; Triacetoneamine-N-Oxyl

Tempidone is original Bulgarian preparation, synthetized in NIHFI (Zelayskov Bikova). The plasma level of the preparation is determined after single oral administration in doses of 60 and 120 mg and for a period of five days in a dose of 20 mg three times daily per a person. It is shown that tempidone is quickly resorbed and is excreted unchanged mainly in urine. The preparation does not cumulate. The content of tempidone in plasma is determined by the method of thin-layer chromatography, but in urine-spectrophotometricaly.

Topics: Administration, Oral; Biopharmaceutics; Dose-Response Relationship, Drug; Drug Evaluation; Humans; Piperidines; Piperidones; Time Factors; Triacetoneamine-N-Oxyl

Topics: Piperidines; Piperidones; Plants; Triacetoneamine-N-Oxyl

Topics: Animals; Barbiturates; Dogs; Drug Synergism; Drug Tolerance; Humans; Mice; Piperidines; Piperidones; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders; Tosyl Compounds; Tranquilizing Agents; Triacetoneamine-N-Oxyl

Topics: Animals; Anti-Anxiety Agents; Central Nervous System; Male; Mice; Pentylenetetrazole; Piperidines; Piperidones; Receptors, Cholinergic; Strychnine; Tosyl Compounds; Triacetoneamine-N-Oxyl

Topics: Animals; Brain; Female; In Vitro Techniques; Ketoglutaric Acids; Male; Mitochondria; Mitochondria, Liver; Oxidative Phosphorylation; Piperidines; Piperidones; Rats; Tosyl Compounds; Triacetoneamine-N-Oxyl

Topics: Administration, Oral; Aggression; Animals; Avoidance Learning; Brain; Cats; Central Nervous System; Chlorpromazine; Columbidae; Drug Synergism; Ganglionic Blockers; Hexobarbital; Humans; Hydroxyzine; Injections, Intraperitoneal; Ketones; Mice; Morpholines; Motor Activity; Opipramol; Piperidines; Rabbits; Rats; Tosyl Compounds; Triacetoneamine-N-Oxyl

Topics: Animals; Chemistry, Pharmaceutical; Dogs; Lagomorpha; Mice; Pharmacy; Piperidines; Rabbits; Research; Toxicology; Triacetoneamine-N-Oxyl