The glutamate receptor GluR5 agonist (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid and the 8-methyl analogue: synthesis, molecular pharmacology, and biostructural characterization.
The design, synthesis, and pharmacological characterization of a highly potent and selective glutamate GluR5 agonist is reported. (S)-2-Amino-3-((RS)-3-hydroxy-8-methyl-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid (5) is the 8-methyl analogue of (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid ((S)-4-AHCP, 4). Compound 5 displays an improved selectivity profile compared to 4. A versatile stereoselective synthetic route for this class of compounds is presented along with the characterization of the binding affinity of 5 to ionotropic glutamate receptors (iGluRs). Functional characterization of 5 at cloned iGluRs using a calcium imaging assay and voltage-clamp recordings show a different activation of GluR5 compared to (S)-glutamic acid (Glu), kainic acid (KA, 1), and (S)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl)propionic acid ((S)-ATPA, 3) as previously demonstrated for 4. An X-ray crystallographic analysis of 4 and computational analyses of 4 and 5 bound to the GluR5 agonist binding domain (ABD) are presented, including a watermap analysis, which suggests that water molecules in the agonist binding site are important selectivity determinants.
Clausen
Rasmus P
RP
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100 Copenhagen, Denmark. rac@farma.ku.dk
Naur
Peter
P
Kristensen
Anders S
AS
Greenwood
Jeremy R
JR
Strange
Mette
M
Bräuner-Osborne
Hans
H
Jensen
Anders A
AA
Nielsen
Anne Sophie T
AS
Geneser
Ulla
U
Ringgaard
Lone M
LM
Nielsen
Birgitte
B
Pickering
Darryl S
DS
Brehm
Lotte
L
Gajhede
Michael
M
Krogsgaard-Larsen
Povl
P
Kastrup
Jette S
JS
D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D018690:Excitatory Amino Acid Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D011422:Propionates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018092:Kainic Acid Receptors / Q000819:agonists* / Q000737:chemistry / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D018690:Excitatory Amino Acid Agonists; D011422:Propionates; D018092:Kainic Acid Receptors