ABSTRACT
The synthesis of the C1-C19 bis-pyran unit of phorboxazole B has been achieved. The key pyran rings were constructed by means of an asymmetric Maitland-Japp reaction and a second Maitland-Japp resolution/cyclization reaction. The longest linear sequence was 14 steps, and the C1-C19 bis-pyran unit was formed in an impressive 10.4% yield.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Oxazoles/chemical synthesis , Pyrans/chemical synthesis , Cyclization , Heterocyclic Compounds, 4 or More Rings/chemistry , Molecular Structure , Oxazoles/chemistry , Pyrans/chemistryABSTRACT
MeSO3H effects the intramolecular allenylation of a series of aldehydes 1 to provide allenyl alcohol product 3 as a single diastereoisomer. Cyclization proceeds rapidly at -78 degrees C. However, when the reaction is performed at room temperature, aldehyde 1 provides enone product 7 instead. A mechanism for the formation of this product is proposed in which the initially formed allenyl alcohol 3 undergoes dehydration to provide an allyl carbocation, which is trapped with water, thereby installing the enone.
Subject(s)
Acids/chemistry , Aldehydes/chemistryABSTRACT
8-Fluoroimidazo[1,2-a]pyridine has been established as a physicochemical mimic of imidazo[1,2-a]pyrimidine, using both in silico and traditional techniques. Furthermore, a novel synthesis of a 3,7-disubstituted-8-fluoroimidazopyridine 3 has been developed and the utility of the physicochemical mimicry has been demonstrated in an in vitro system. Here, the 8-fluoroimidazopyridine ring contained in ligand 3 acts as a bioisosteric replacement for imidazopyrimidine in the GABA(A) receptor modulator 2.
Subject(s)
Allosteric Regulation/drug effects , GABA Agonists/chemical synthesis , GABA-A Receptor Agonists , Imidazoles/chemical synthesis , Pyridines/chemical synthesis , Animals , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , GABA Agonists/chemistry , GABA Agonists/pharmacology , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Ligands , Mice , Molecular Structure , Pyridines/chemistry , Pyridines/pharmacology , Recombinant Proteins/agonists , Structure-Activity RelationshipABSTRACT
The GABA(A) receptor subtypes responsible for the anxiolytic effects of nonselective benzodiazepines (BZs) such as chlordiazepoxide (CDP) and diazepam remain controversial. Hence, molecular genetic data suggest that alpha2-rather than alpha3-containing GABA(A) receptors are responsible for the anxiolytic effects of diazepam, whereas the anxiogenic effects of an alpha3-selective inverse agonist suggest that an agonist selective for this subtype should be anxiolytic. We have extended this latter pharmacological approach to identify a compound, 4,2'-difluoro-5'-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-á]pyridin-3-yl]biphenyl-2-carbonitrile (TP003), that is an alpha3 subtype selective agonist that produced a robust anxiolytic-like effect in both rodent and non-human primate behavioral models of anxiety. Moreover, in mice containing a point mutation that renders alpha2-containing receptors BZ insensitive (alpha2H101R mice), TP003 as well as the nonselective agonist CDP retained efficacy in a stress-induced hyperthermia model. Together, these data show that potentiation of alpha3-containing GABA(A) receptors is sufficient to produce the anxiolytic effects of BZs and that alpha2 potentiation may not be necessary.
Subject(s)
Anti-Anxiety Agents/therapeutic use , Benzodiazepines/therapeutic use , Protein Subunits/physiology , Receptors, GABA-A/physiology , Animals , Anti-Anxiety Agents/pharmacology , Anxiety/drug therapy , Anxiety/metabolism , Benzodiazepines/pharmacology , Dose-Response Relationship, Drug , GABA-A Receptor Agonists , Humans , Male , Mice , Mice, Transgenic , Protein Binding/physiology , Rats , Rats, Sprague-Dawley , SaimiriABSTRACT
Incorporation of fluorine at the 4-position of an existing series of sulfonyl piperidine 5-HT2A antagonists gave compounds with increased selectivity over the IKr potassium channel. This work led to the identification of 3b, a compound that gave no increase in QTc in the anesthetized dog up to plasma levels as high as 148 microM. Furthermore, 3b has been shown to increase slow-wave sleep bout duration and to decrease the number of awakenings in rats, indicating the potential utility of 5-HT2A antagonists in the treatment of insomnia.
