ABSTRACT
[figure: see text] A tandem anionic 5-exo-dig cyclization/Claisen rearrangement sequence was used to effect a facile, "one-pot" conversion of an appropriately substituted 4-alkyn-1-ol to the tetracyclic carbon core structure of phorbol. The synthesis was conducted using readily available nonracemic starting materials to provide the target structure as a single enantiomer in high chemical yield.
Subject(s)
Polycyclic Compounds/chemistry , Polycyclic Compounds/chemical synthesis , Alkynes/chemistry , Catalysis , Cyclization , Magnetic Resonance Spectroscopy , Molecular Structure , Phorbols/chemistry , Stereoisomerism , Structure-Activity Relationship , Vinyl Compounds/chemistryABSTRACT
The scope and limitations of a tandem 5-exo dig cyclization/Claisen rearrangement sequence involving appropriately substituted 4-alkyn-1-ols as an efficient "one-pot" route to fused tricyclic ring systems is described. The reaction rates were found to be strongly dependent on the nature of the terminal substitutent of the triple bond. In some cases the entire sequence was found to proceed in good yield at temperatures as low as 115 degrees C.
Subject(s)
Cycloheptanes/chemical synthesis , Polycyclic Compounds/chemical synthesis , Cyclization , Cycloheptanes/chemistry , Kinetics , Polycyclic Compounds/chemistry , TemperatureABSTRACT
We compared mu- and delta-opioid receptor distributions between the brains of alcohol-preferring Alko, Alcohol (AA) and alcohol-avoiding Alko, Non-Alcohol (ANA) rat lines, using autoradiography on brain sections with mu- and delta-opioid receptor antagonist ligands [3H]CTOP and [3H]naltrindole, respectively. The labeling patterns of the ligands were consistent with the known opioid receptor distributions in both rat lines and no major genetic differences were found between the lines. However, the binding density of mu- and delta-opioid receptors differed slightly in several brain areas: in the AA brain sections, limbic areas, such as hippocampus and amygdala, showed decreased mu- and delta-opioid receptor binding, whereas the striatal patches were larger and the substantia nigra showed higher binding density of the mu-receptors compared to the ANA sections. The small differences observed between the rat lines could be due to adaptations to altered endogenous opioid peptide levels or neural circuits, and associated with the differences in alcohol drinking or other behaviors.
Subject(s)
Alcohol Drinking/genetics , Brain/metabolism , Food Preferences , Naltrexone/analogs & derivatives , Receptors, Opioid/metabolism , Somatostatin/analogs & derivatives , Amygdala/metabolism , Animals , Autoradiography , Corpus Striatum/metabolism , Hippocampus/metabolism , Male , Naltrexone/metabolism , Narcotic Antagonists/metabolism , Rats , Rats, Mutant Strains , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/metabolism , Somatostatin/metabolism , Substantia Nigra/metabolism , TritiumABSTRACT
Compounds interacting with the GABA(A) receptor system modulate voluntary alcohol consumption in alcohol-preferring AA (Alko, Alcohol) rats. Therefore, we compared the central GABA(A) receptor pharmacology of the AA rats to that of their counterpart, alcohol-avoiding ANA (Alko, Non-Alcohol) rats with receptor autoradiography. Total flumazenil-sensitive [(3)H]Ro 15-4513 binding to the benzodiazepine site of GABA(A) receptor was slightly lower in the hippocampus, striate cortex and lateral hypothalamus of the AA than ANA rats. The proportions of zolpidem- and diazepam-sensitive components were similar in both rat lines. Basal picrotoxin-sensitive [(35)S]TBPS binding to the convulsant site of GABA(A) receptor was similar in most regions between the rat lines, but the up-modulation of the binding by 10 microM diazepam in the hippocampal, amygdaloid and entorhinal cortical areas was greater in the AA than ANA rats. These results do not reveal any general genetic defect in the GABA(A) receptors of AA or ANA rats, but the regional profile of the ligand binding differences between the lines, especially in the coupling of the benzodiazepine and chloride channel sites, suggests receptor subtype-specific changes in brain regions implicated in behavioural reward and anxiolysis.
ABSTRACT
Brain opioidergic mechanisms participate in the regulation of motivational and ingestive behaviours. Since alcohol is believed to activate endogenous opioid systems and to produce opioid-mediated antinociception, the present experiments were performed to find out if alcohol-induced antinociception differs between the alcohol-preferring AA and alcohol-avoiding ANA rat lines. Alcohol doses relevant to the voluntary alcohol intake by the AA rats (0.5-1.0 g/kg, intraperitoneally) failed to alter tail-flick (TF) latency in a 55 degrees C water bath by either rat line. However, repeated measurement of TF latency, even without any alcohol treatment, prolonged tail-flick latencies in AA but not in ANA rats. Prolongation of TF latency was also seen in non-selected Wistar rats, indicating that the ANA rats respond abnormally in this test. The antinociceptive effects of swimming-induced stress (3 min at 15 degrees C) and those of cumulative morphine administration (0.5-16.0 mg/kg, subcutaneously) were similar in both rat lines. Using higher, motor-impairing alcohol doses with repeated baseline TF determinations, it was observed that a dose of 1.5 g/kg induced slight antinociception only in the AA rats, while 2.0 g/kg produced similar effects in both rat lines. It is thus concluded that the alcohol-preferring AA rats do not show any enhanced alcohol-induced antinociception at relevant alcohol doses. However, the alcohol-avoiding ANA rats appear to have a defective ability to habituate to repeated sensory stimuli, which could contribute to their alcohol avoidance by preventing the development of tolerance to aversive effects of alcohol.
Subject(s)
Ethanol/pharmacology , Habituation, Psychophysiologic , Narcotics/pharmacology , Nociceptors/drug effects , Alcohol Drinking , Analgesia , Animals , Behavior, Animal/drug effects , Dose-Response Relationship, Drug , Male , Rats , Rats, Wistar , Stress, Physiological , Time FactorsABSTRACT
A selective breeding program has led to the establishment of the alcohol-preferring AA (Alko, Alcohol) and alcohol-avoiding ANA (Alko, Nonalcohol) rat lines. To reveal putative baseline differences in dopamine receptor gene expression and dopamine receptor binding profile in the AA and ANA rat lines, we assessed striatal D2 mRNA levels in these two rat lines. Autoradiographical studies on dopamine D1 and D2 receptors in the striatum and nucleus accumbens were also performed with [3H]SCH 23390 and [125I]iodosulpiride/[3H]spiperone, respectively. The baseline differences in D1 or D2 receptor binding and D2 receptor gene expression between AA and ANA rat lines are marginal, and are not likely to play a role in the genetic background of the differential alcohol drinking behavior of these rat lines.
