ABSTRACT
Cocaine, a potent stimulant of the central nervous system, owes its reinforcing and stimulant properties to its ability to inhibit monoamine uptake systems such as the Dopamine Transporter (DAT), and the Serotonin Transporter (SERT) located on presynaptic neurons in the striatum. The search for pharmacotherapies for cocaine addiction has focused on the design of compounds that bind selectively to the DAT and manifest slow onset of stimulatory action with long duration of action. We had reported that 3-aryl-2-carbomethoxy-8-thiabicyclo[3.2.1]octanes are potent and selective inhibitors of the DAT. In this Letter we report on the effects of replacement of the 2-carbomethoy group by a 2-isoxazole. This new class of 8-thiabicyclo[3.2.1]octanes provides potent and selective inhibitors of the DAT. The 3ß-aryl compounds are particularly potent inhibitors of DAT (IC(50) = 7-43 nM) with substantial selectivity versus inhibition of SERT.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Dopamine Uptake Inhibitors/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/pharmacology , Humans , Isoxazoles/chemistry , Protein Binding , Serotonin Plasma Membrane Transport Proteins/chemistry , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacologyABSTRACT
Dihydrosiloles are easily prepared from 1,3-dienes and dichlorosilanes, even on kilogram scale. Asymmetric hydroboration of a 3-alkyl-1,5-dihydrosilole, prepared from a 2-alkyl-1,3-diene, followed by treatment with aqueous HF results in Peterson fragmentation, forming optically active 3-alkyl-4-fluorosilyl-1-butenes. The fluorosilanes are stable to moisture but very reactive toward nucleophiles. In addition, they can be converted to nucleophilic silyllithium reagents.
Subject(s)
Silanes/chemistry , Alkadienes/chemistry , Molecular Structure , Silanes/chemical synthesis , StereoisomerismABSTRACT
Structurally diverse carbon-linked (C-linked) analogs of antifreeze glycoprotein (AFGP) have been prepared via linear or convergent solid phase synthesis. These analogs range in molecular weight from approx 1.5-4.1 KDa and do not possess the beta-D-galactose-1,3-alpha-D-N-acetylgalactosamine carbohydrate moiety or the L-threonine-L-alanine-L-alanine polypeptide backbone native to the AFGP wild-type. Despite these dramatic structural modifications, the 2.7-KDa and 4.1-KDa analogs possess antifreeze protein-specific activity as determined by recrystallization-inhibition (RI) and thermal hysteresis (TH) assays. These analogs are weaker than the wild-type in their activity, but nanoliter osmometry indicates that these compounds are binding to ice and affecting a localized freezing point depression. This is the first example of a C-linked AFGP analog that possesses TH and RI activity and suggests that the rational design and synthesis of chemically and biologically stable AFGP analogs is a feasible and worthwhile endeavor. Given the low degree of TH activity, these compounds may prove useful for the protection of cells during freezing and thawing cycles.
