piperidines and pipradrol

Between 1997 and 2011, more than 200 new substances were notified through the early-warning system, with the record number of 49 novel molecules reported in 2011. The pattern of acute toxicity associated with the consumption of these new substances is generally similar to that seen with traditional drugs of abuse. Recently, a new class of synthetic stimulants closely related to pyrrolidine and piperidine compounds and known as pipradrol derivatives appeared in the recreational drug market. These substances, producing amphetamine-like effects, are used by people in substitution of traditional illicit drugs. The aim of this paper is to summarize the clinical, pharmacological and toxicological information currently available about this new class of synthetic drugs of abuse.

Topics: Humans; Illicit Drugs; Piperidines

Topics: Amitriptyline; Amphetamine; Amphetamines; Antidepressive Agents; Aspartic Acid; Benactyzine; Classification; Deanol; Depression; Desipramine; Humans; Imipramine; Isocarboxazid; Methylphenidate; Monoamine Oxidase Inhibitors; Nialamide; Pargyline; Pharmacology; Phenelzine; Phenmetrazine; Piperidines; Sympathomimetics; Toxicology; Tranylcypromine

Aminoindanes, piperazines, and pipradrol derivatives are novel psychoactive substances found in "Ecstasy" tablets as replacements for 3,4-methylenedioxymethamphetamine (MDMA) or substances sold as "ivory wave." The pharmacology of these MDMA- and methylphenidate-like substances is poorly known. We characterized the pharmacology of the aminoindanes 5,6-methylenedioxy-2-aminoindane (MDAI), 5-iodoaminoindane (5-IAI), and 2-aminoindane (2-AI), the piperazines meta-chlorophenylpiperazine (m-CPP), trifluoromethylphenylpiperazine (TFMPP), and 1-benzylpiperazine (BZP), and the pipradrol derivatives desoxypipradrol (2-diphenylmethylpiperidine [2-DPMP]), diphenylprolinol (diphenyl-2-pyrrolidinemethanol [D2PM]), and methylphenidate. We investigated norepinephrine (NE), dopamine (DA), and serotonin (5-hydroxytryptamine [5-HT]) uptake inhibition using human embryonic kidney 293 (HEK 293) cells that express the respective human monoamine transporters (NET, DAT, and SERT). We also evaluated the drug-induced efflux of NE, DA, and 5-HT from monoamine-preloaded cells and the binding affinity to monoamine transporters and receptors, including trace amine-associated receptor 1 (TAAR1). 5-IAI and MDAI preferentially inhibited the SERT and NET and released 5-HT. 2-AI interacted with the NET. BZP blocked the NET and released DA. m-CPP and TFMPP interacted with the SERT and serotonergic receptors. The pipradrol derivatives were potent and selective catecholamine transporter blockers without substrate releasing properties. BZP, D2PM, and 2-DPMP lacked serotonergic activity and TAAR1 binding, in contrast to the aminoindanes and phenylpiperazines. In summary, all of the substances were monoamine transporter inhibitors, but marked differences were found in their DAT vs. SERT inhibition profiles, release properties, and receptor interactions. The pharmacological profiles of D2PM and 2-DPMP likely predict a high abuse liability.

Topics: HEK293 Cells; Humans; Indans; Piperazines; Piperidines; Protein Binding; Vesicular Monoamine Transport Proteins

The picolinoxy group was found to be an extremely powerful leaving group for allylic substitution with aryl nucleophiles derived from ArMgBr and CuBr*Me2S. The substitution proceeds with anti SN2' pathway and with high chirality transfer. The electron-withdrawing effect of the pyridyl group and chelation to MgBr2 are likely the origin of success. Results suggesting these effects were obtained.

Topics: Allyl Compounds; Anions; Indicators and Reagents; Molecular Structure; Picolinic Acids; Piperidines; Stereoisomerism

The weakly alkylating capacity of phosphotriesters (PTE) has been used for the determination of adducts to phosphate groups in DNA by specific transfer to the strongly nucleophilic compound cob(I)alamin [Cbl(I)]. When enzymatically degraded liver DNA from mice treated with 1-(N-methyl-N-nitrosamino)-4-(3-[3H]pyridyl)-4-oxobutane ([3H]NNK) was added to Cbl(I), a 4-(3-[3H]pyridyl)-4-hydroxy-1-butyl-cobalamin ([3H]PHB-Cbl) complex was formed and determined by HPLC and liquid scintillation counting. The PHB-Cbl formed was compared with a synthetic standard verified by LC/MS and 1H NMR and corresponds to phosphate adducts formed from the pyridyloxobutylating species from NNK and from the pyridylhydroxybutylating species from NNAL, NNK being to a large extent converted to NNAL in vivo. It was concluded that about 22% of the total level of pyridyl (oxo or hydroxy) butyl adducts to DNA was bound to phosphate groups.

Topics: Alkylation; Animals; Biotransformation; Carcinogens; Chromatography, High Pressure Liquid; DNA; DNA Adducts; Hydroxylation; Liver; Mice; Nitrosamines; Phosphates; Phosphoric Diester Hydrolases; Piperidines; Spectrophotometry, Ultraviolet; Vitamin B 12

The nucleus accumbens, a site within the ventral striatum, is best known for its prominent role in mediating the reinforcing effects of drugs of abuse such as cocaine, alcohol, and nicotine. Indeed, it is generally believed that this structure subserves motivated behaviors, such as feeding, drinking, sexual behavior, and exploratory locomotion, which are elicited by natural rewards or incentive stimuli. A basic rule of positive reinforcement is that motor responses will increase in magnitude and vigor if followed by a rewarding event. It is likely, therefore, that the nucleus accumbens may serve as a substrate for reinforcement learning. However, there is surprisingly little information concerning the neural mechanisms by which appetitive responses are learned. In the present study, we report that treatment of the nucleus accumbens core with the selective competitive N-methyl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonopentanoic acid (AP-5; 5 nmol/0.5 microl bilaterally) impairs response-reinforcement learning in the acquisition of a simple lever-press task to obtain food. Once the rats learned the task, AP-5 had no effect, demonstrating the requirement of NMDA receptor-dependent plasticity in the early stages of learning. Infusion of AP-5 into the accumbens shell produced a much smaller impairment of learning. Additional experiments showed that AP-5 core-treated rats had normal feeding and locomotor responses and were capable of acquiring stimulus-reward associations. We hypothesize that stimulation of NMDA receptors within the accumbens core is a key process through which motor responses become established in response to reinforcing stimuli. Further, this mechanism, may also play a critical role in the motivational and addictive properties of drugs of abuse.

Topics: 2-Amino-5-phosphonovalerate; Animals; Antidepressive Agents; Appetitive Behavior; Behavior, Animal; Conditioning, Operant; Dopamine; Excitatory Amino Acid Antagonists; Feeding Behavior; Food Deprivation; Locomotion; Male; N-Methylaspartate; Nucleus Accumbens; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Reinforcement, Psychology

Topics: Animals; Behavior, Animal; Brain; Brain Chemistry; Cocaine; Dextroamphetamine; Dopamine; Iproniazid; Metabolism; Mice; Motor Activity; Movement; Norepinephrine; Pharmacology; Piperidines; Research; Reserpine; Serotonin

Topics: Amitriptyline; Antidepressive Agents; Central Nervous System Stimulants; Chlorpromazine; Chlorprothixene; Cocaine; Desipramine; Humans; Imipramine; Male; Methylphenidate; Norepinephrine; Pharmacology; Phenmetrazine; Piperidines; Rats; Research; Tranquilizing Agents; Vas Deferens

Topics: Blood Pressure; Cocaine; Dogs; Ephedrine; Guanethidine; Heart; Heart Rate; Isomerism; Methylphenidate; Pharmacology; Piperidines; Research

Topics: Amobarbital; Diethylpropion; Environment; Humans; Mental Disorders; Piperidines; Psychopharmacology

Topics: Adolescent; Amphetamine; Amphetamines; Atropa belladonna; Bromides; Child; Enuresis; Humans; Imipramine; Meprobamate; Methantheline; Methylphenidate; Piperidines; Quaternary Ammonium Compounds; Reserpine; Sympathomimetics

Topics: Conditioning, Classical; Dogs; Nervous System Physiological Phenomena; Neurotic Disorders; Pharmacology; Piperidines; Reflex; Research

Topics: Amitriptyline; Animals; Antidepressive Agents; Brain; Catecholamines; Chlorpromazine; Cocaine; Desipramine; Dogs; Dopamine; Electric Stimulation; Electrophysiology; Guanethidine; Imipramine; Metaraminol; Methylphenidate; Mice; Myocardium; Nictitating Membrane; Norepinephrine; Pharmacology; Piperidines; Promazine; Research; Reserpine; Tripelennamine; Tyrosine

Topics: Amitriptyline; Amphetamine; Amphetamines; Barbiturates; Benactyzine; Chlordiazepoxide; Deanol; Depression; Depressive Disorder; Diagnosis; Diazepam; Drug Therapy; Geriatrics; Humans; Imipramine; Meprobamate; Methylphenidate; Monoamine Oxidase Inhibitors; Phenmetrazine; Piperidines; Psychotherapy; Toxicology

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: Behavior, Animal; Caffeine; Chlordiazepoxide; Chlorpromazine; Dextroamphetamine; Methylphenidate; Motor Activity; Movement; Pharmacology; Phenmetrazine; Piperidines; Prochlorperazine; Rats; Research; Tranylcypromine; Trifluoperazine

Topics: Animals; Behavior, Animal; Birds; Cocaine; Columbidae; Conditioning, Psychological; Dextroamphetamine; Imipramine; Movement; Piperidines; Psychopharmacology; Research; Reserpine

Topics: Amphetamine; Amphetamines; Anesthetics; Animals; Behavior, Animal; Chlorpromazine; Indoles; Lysergic Acid Diethylamide; Mescaline; Pentobarbital; Phenelzine; Piperidines; Psychotropic Drugs; Rats; Research; Reserpine

Topics: Amphetamine; Amphetamines; Animals; Avoidance Learning; Behavior, Animal; Caffeine; Central Nervous System Stimulants; Hydrazines; Methylphenidate; Noise; Pharmacology; Piperidines; Rats; Research; Tranylcypromine

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

Topics: Antihypertensive Agents; Brain; Cocaine; Dextroamphetamine; Dihydroxyphenylalanine; Dopamine; Locomotion; Methyldopa; Mice; Motor Activity; Pharmacology; Piperidines; Research; Reserpine; Serotonin

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: Adolescent; Child; Electroencephalography; Humans; Piperidines; Schizophrenia

Topics: Behavior; Chlorpromazine; Conditioning, Classical; Conditioning, Operant; Piperidines; Reflex

Topics: Brain; Electroencephalography; Humans; Phenothiazines; Piperidines

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: Central Nervous System Stimulants; Generalization, Stimulus; Humans; Learning; Piperidines

Topics: Basal Metabolism; Depression; Depressive Disorder; Piperidines

Topics: Depth Perception; Humans; Piperidines; Visual Perception

Topics: Chlorpromazine; Dementia; Humans; Mental Disorders; Opium; Piperidines; Psychopharmacology; Psychotic Disorders; Reserpine

Topics: Humans; Piperidines; Research; Schizophrenia

Topics: Amides; Central Nervous System Stimulants; Deanol; Pentylenetetrazole; Picrotoxin; Piperidines; Psychopharmacology; Vanillic Acid

Topics: Benzhydryl Compounds; Methylphenidate; Piperidines; Schizophrenia

Topics: Methylphenidate; Piperidines

Topics: Alcohol Drinking; Alcoholism; Animals; Methylphenidate; Piperidines; Rats; Tranquilizing Agents

Topics: Central Nervous System; Piperidines

Topics: Amobarbital; Central Nervous System Agents; Central Nervous System Stimulants; Humans; Learning; Piperidines; Reactive Inhibition

Topics: Behavior; Central Nervous System Stimulants; Humans; Meprobamate; Methylphenidate; Piperidines; Tranquilizing Agents

Topics: Electroencephalography; Mental Disorders; Piperidines

Topics: Piperidines; Schizophrenia

Topics: Amphetamine; Amphetamines; Central Nervous System Stimulants; Iproniazid; Methylphenidate; Movement Disorders; Niacin; Nicotinic Acids; Piperidines

Topics: Aged; Anxiety; Anxiety Disorders; Disease; Humans; Piperidines; Psychomotor Agitation; Reserpine

Topics: Humans; Obesity; Piperidines

Topics: Central Nervous System Stimulants; Humans; Methylphenidate; Piperidines

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

Topics: Emotions; Humans; Piperidines; Psychotropic Drugs

Topics: Electroconvulsive Therapy; Mental Disorders; Piperidines; Psychotherapy

Topics: Aged; Depression; Depressive Disorder; Fatigue; Humans; Patients; Piperidines

Topics: Bipolar Disorder; Chlorpromazine; Depression; Depressive Disorder, Major; Methylphenidate; Piperidines; Psychotic Disorders

Topics: Bacteria; Piperidines

Topics: Hospitals, State; Humans; Mental Disorders; Methylphenidate; Piperidines; Psychosurgery; Psychotherapy; Tranquilizing Agents

Topics: Aged; Biomedical Research; Diet; Geriatrics; Humans; Piperidines

Topics: Brain; Electroencephalography; Humans; Nervous System Physiological Phenomena; Piperidines

Topics: Diet, Reducing; Intellectual Disability; Piperidines

Topics: Central Nervous System Stimulants; Depression; Depressive Disorder; Female; Genital Diseases, Female; Gynecology; Humans; Obstetrics; Piperidines

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

Topics: Mental Disorders; Piperidines; Psychosurgery; Psychotherapy; Reserpine

Topics: Piperidines

Topics: Depression; Depressive Disorder; Piperidines

Topics: Depression; Depressive Disorder; Piperidines

Topics: Benzhydryl Compounds; Central Nervous System Stimulants; Obesity; Piperidines