Diastereoselective synthesis of all four isomers of 3-(4-chlorophenyl) glutamic acid: identification of the isomers responsible for the potentiation of L-homocysteic acid-evoked depolarizations in neonatal rat motoneurons.
All four isomers of 3-(4-chlorophenyl)glutamic acid (5-8) were prepared by diastereoselective synthesis. Addition of (6S)-(+)-bis-lactim ether 15 to cis-4-chlorocinnamate 12 gave a mixture comprising mainly the (2R,3S)- and (2R,3R)-isomers 5 and 6, respectively (in a ratio of 56:40), while addition of (6R)-(-)-bis-lactim ether 16 to 4-chlorocinnamate 12 gave a mixture comprising mainly the (2S,3R)- and (2S,3S)-isomers 8 and 7, respectively (in a ratio of 56:42). The four stereoisomers (5-8) were therefore conveniently prepared by addition of either 3-lithio-(6S)- or -(6R)-bis-lactim ether (15 or 16, respectively) to 4-chlorocinnamate 12 and separation of the resultant mixtures of diastereoisomers (23-26) by flash silica gel chromatography. The absolute configurations of 6 and 7 were confirmed by X-ray crystallography. Both the (2S,3S)- and (2S,3R)-isomers (7 and 8, respectively) at a concentration of 100 microM significantly potentiated depolarizations induced by 10 microM L-homocysteic acid (L-HCA) (% control +/- sem: 130.4 +/- 3.6, n = 20 and 114.5 +/- 2.4, n = 11, respectively) while the (2R,3S)-isomer 5 significantly reduced L-HCA response amplitude (94.2 +/- 1.4, n = 9) and the (2R,3R)-isomer 6 was inactive. Experiments designed to compare the agonist-potentiating actions of 7 and 8 in the neonatal rat spinal cord with L-trans-pyrrolidine-2,4-dicarboxylic acid, the well-known L-Glu uptake inhibitor, provided additional evidence for the selective enhancement of depolarizations due to L-HCA and not those due to L-Glu. This selective action supports the existence of multiple excitatory amino acid uptake sites.
Jane
D E
DE
Department of Pharmacology, School of Medical Sciences, Bristol, U.K.
Chalmers
D J
DJ
Howard
J A
JA
Kilpatrick
I C
IC
Sunter
D C
DC
Thompson
G A
GA
Udvarhelyi
P M
PM
Wilson
C
C
Watkins
J C
JC
D000818:Animals; D018360:Crystallography, X-Ray; D004594:Electrophysiology; D005971:Glutamates / Q000138:chemical synthesis* / Q000494:pharmacology*; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013116:Spinal Cord; D013237:Stereoisomerism
D005971:Glutamates; D018377:Neurotransmitter Agents; D006710:Homocysteine; C007956:homocysteic acid; D018698:Glutamic Acid; C045418:3-(4-chlorophenyl)glutamic acid