Convergent synthesis and pharmacology of substituted tetrazolyl-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid analogues.
The synthesis and pharmacological characterization of 1- and 2-alkyltetrazolyl analogues of (RS)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-5-tetrazolyl)-4-isoxazolyl]propionic acid (2-Me-Tet-AMPA), a highly potent and selective agonist at AMPA receptors, are presented. A shorter and more convergent synthetic route than previously described, employing a new method for introducing the amino acid moiety, was developed for these derivatives. The 2-substituted isomers were selective agonists, and their activity correlated inversely with the size of the substituent. Structural explanations of the structure-activity relationship are provided.
Vogensen
Stine B
SB
Department of Medicinal Chemistry and Department of Pharmacology, The Danish University of Pharmaceutical Sciences, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
Clausen
Rasmus P
RP
Greenwood
Jeremy R
JR
Johansen
Tommy N
TN
Pickering
Darryl S
DS
Nielsen
Birgitte
B
Ebert
Bjarke
B
Krogsgaard-Larsen
Povl
P
D000818:Animals; D001921:Brain / Q000378:metabolism; D066298:In Vitro Techniques; D008958:Models, Molecular; D011869:Radioligand Assay; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists* / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
D018091:Receptors, AMPA; D013777:Tetrazoles; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid