piperidines and barbituric-acid

A practical and efficient synthesis of spirobarbiturates of type III is reported when NH acidity of the imide function of the hydrophilic linker element allowed the introduction of different substituents. Structural characterization, which was based on both X-ray crystallography and spectroscopic investigations, indicated type II beta-turn formation. Introduction of the molecular scaffold into solid phase peptide synthesis gave rise to spirocyclic neuropeptide analogs.

Topics: Barbiturates; Crystallography, X-Ray; Models, Molecular; Molecular Structure; Piperidines; Proline; Spiro Compounds

Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as gamma-aminobutyric acid(A) (GABA(A)). Two neurosteroids, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. A previous study examining the discriminative stimulus effects of 10 mg/kg pregnanolone in DBA/2J and C57BL/6J mice showed pregnanolone's discriminative stimulus to be mediated primarily through GABA(A) positive modulation. This study examined the discriminative stimulus effects of a lower training dose (5.6 mg/kg) of pregnanolone in DBA/2J and C57BL/5J mice. Twelve male DBA/2J mice and 12 male C57BL/6J mice were trained to discriminate 5.6 mg/kg pregnanolone. GABA(A)-receptor positive modulators, neuroactive steroids, NMDA receptor antagonists, and 5-HT(3) receptor agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for pregnanolone. In the DBA/2J mice, NMDA receptor antagonists showed generalization to the discriminative stimulus cues of pregnanolone, an effect not seen in the C57BL/6J mice. 5-HT(3) receptor agonists and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either strain. AlloTHDOC and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest GABA(A)-receptor positive modulation as the predominant receptor mechanism mediating the discriminative stimulus effects of pregnanolone. NMDA receptor antagonism was suggested in the DBA/2J mice and may represent a heterogenous cue produced by the lower training dose of pregnanolone.

Topics: Animals; Barbiturates; Benzodiazepines; Discrimination, Psychological; Dizocilpine Maleate; Ethanol; GABA Agents; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Piperidines; Pregnanolone; Receptors, N-Methyl-D-Aspartate; Serotonin Receptor Agonists

Topics: Barbiturates; Morphine; Piperidines; Thiazoles

Topics: Barbiturates; Bemegride; Piperidines; Thiazoles

Topics: Barbiturates; Humans; Picrotoxin; Piperidines

Topics: Barbiturates; Bemegride; Piperidines; Poisoning

Topics: Barbiturates; Bemegride; Piperidines

Topics: Barbiturates; Bemegride; Chlorpromazine; Codeine; Hydrocodone; Piperidines; Psychotropic Drugs; Thiazoles

Topics: Barbiturates; Piperidines

Topics: Barbiturates; Piperidines; Poisoning; Thiazoles

Topics: Barbiturates; Bemegride; Piperidines; Poisoning

Topics: Barbiturates; Central Nervous System Stimulants; Piperidines; Poisoning; Thiazoles

Topics: Barbiturates; Piperidines