Aryl and cycloalkyl analogues of AMPA: synthetic, pharmacological and stereochemical aspects.
We have previously shown that (RS)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA, 2) is a functional partial agonist at the (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) subtype of excitatory amino acid receptors, reflecting that (S)-APPA is a full agonist and (R)-APPA a competitive antagonist at AMPA receptors. We have now synthesized and pharmacologically characterized (RS)-2-amino-3-[3-hydroxy-5-(2-fluorophenyl)isoxazol-4-yl]propioni c acid (2-F-APPA, 5a), 3-F-APPA (5b), 4-F-APPA (5c), (S)-4-F-APPA (6), (R)-4-F-APPA (7), and the fully and partially, respectively, saturated APPA (2) analogues, (RS)-2-amino-3-(3-hydroxy-5-cyclohexylisoxazol-4-yl)propionic acid (5d) and compound 5e containing a 1-cyclohexenyl ring. The absolute stereochemistry of 6 and 7 was established on the basis of comparative circular dichroism studies on 6, 7, and (S)- and (R)-APPA. 4-F-APPA (5c), (S)-4-F-APPA (6), 5d, and 5e were shown to selectively inhibit [3H]AMPA binding and to activate AMPA receptors. Whereas (S)-4-F-APPA (6) showed full AMPA receptor agonism, (R)-4-F-APPA (7) was an AMPA receptor antagonist. Co-administration of (S)- and (R)-4-F-APPA to the rat cortical wedge preparation produced functional partial AMPA receptor agonism. Semi empirical calculations showed that the magnitude of the torsional angle of the bond connecting the two rings in the series of nonannulated bicyclic AMPA analogues appears to be of importance for the potency and efficacy of these compounds.
Skjaerbaek
N
N
PharmaBiotec Research Centre, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Copenhagen, Denmark.
Brehm
L
L
Johansen
T N
TN
Hansen
L M
LM
Nielsen
B
B
Ebert
B
B
Søby
K K
KK
Stensbøl
T B
TB
Falch
E
E
Krogsgaard-Larsen
P
P
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002942:Circular Dichroism; D003337:Corpus Callosum / Q000187:drug effects / Q000378:metabolism; D015226:Dinucleoside Phosphates / Q000737:chemistry / Q000494:pharmacology*; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000819:agonists / Q000031:analogs & derivatives* / Q000494:pharmacology
D015226:Dinucleoside Phosphates; D018690:Excitatory Amino Acid Agonists; D018091:Receptors, AMPA; C012276:diadenosine pyrophosphate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid