Abstract
As part of a program aimed at generating compounds with affinity for the alpha(2)-delta subunit of voltage-gated calcium channels, several novel beta-amino acids were prepared using an efficient nitroalkane-mediated cyclopropanation as a key step. Depending on the ester that was chosen, the target amino acids could be prepared in as few as three steps. The cyclopropyl amino acids derived from ketones proved to be potent binders of the alpha(2)-delta subunit of voltage-gated calcium channels, but did not interact with the large neutral amino acid system L (leucine) transporter. Anticonvulsant effects were observed in vivo with compound 34 but only after intracerebroventricular (icv) administration, presumably due to inadequate brain concentrations of the drug being achieved following oral dosing. However, pregabalin 1 was active in the DBA/2 model after oral (and icv) dosing, supporting a hypothesis that active transport is a prerequisite for such zwitterionic species to cross the blood-brain barrier.
MeSH terms
-
Administration, Oral
-
Amines / chemical synthesis*
-
Amines / chemistry
-
Amines / pharmacology
-
Amino Acid Transport System L / metabolism
-
Amino Acids / chemistry*
-
Animals
-
Anticonvulsants / chemical synthesis
-
Anticonvulsants / chemistry
-
Anticonvulsants / pharmacology
-
Biological Transport, Active
-
Blood-Brain Barrier / metabolism
-
CHO Cells
-
Calcium Channels / drug effects*
-
Calcium Channels / metabolism
-
Cricetinae
-
Cricetulus
-
Cyclization
-
Cyclohexanecarboxylic Acids / chemical synthesis*
-
Cyclohexanecarboxylic Acids / chemistry
-
Cyclohexanecarboxylic Acids / pharmacology
-
Cyclopropanes / chemical synthesis*
-
Cyclopropanes / chemistry
-
Cyclopropanes / pharmacology
-
Gabapentin
-
In Vitro Techniques
-
Injections, Intraventricular
-
Ion Channel Gating
-
Male
-
Mice
-
Mice, Inbred DBA
-
Nitriles / chemistry
-
Pregabalin
-
Protein Subunits / metabolism
-
Rats
-
Rats, Sprague-Dawley
-
Swine
-
gamma-Aminobutyric Acid / analogs & derivatives*
-
gamma-Aminobutyric Acid / chemical synthesis*
-
gamma-Aminobutyric Acid / chemistry
-
gamma-Aminobutyric Acid / pharmacology
Substances
-
Amines
-
Amino Acid Transport System L
-
Amino Acids
-
Anticonvulsants
-
Calcium Channels
-
Cyclohexanecarboxylic Acids
-
Cyclopropanes
-
Nitriles
-
Protein Subunits
-
Pregabalin
-
gamma-Aminobutyric Acid
-
Gabapentin