TY - JOUR
T1 - α-Substituted quisqualic acid analogs
T2 - New metabotropic glutamate receptor group II selective antagonists
AU - Kozikowski, Alan P.
AU - Steensma, Darryl
AU - Varasi, Mario
AU - Pshenichkin, Sergey
AU - Surina, Elena
AU - Wroblewski, Jarda T.
N1 - Funding Information:
individual mGluR subtypes (Table 1 and Figure 2). t~-Methylquisqualate (MetQuis) was a competitive antagonist of group II mGluRs as shown by its ability to inhibit the action of increasing concentrations of ACPD. The calculated K B for MetQuis was 40 jaM. It was less potent as an antagonist of mGluR5a and mGluRla, and it had no activity at mGluR4a and mGluR6. Similarly, t~-benzylquisqualate (BnQuis) antagonized mGluR2 receptors with an improved potency (K B= 7.1 ~VI) over that of MetQuis, while it had little activity at group I receptors and no activity at mGluR4a and mGluR6. Both compounds were also tested for activity at ionotropic glutamate receptors and were found to partially antagonize NMDA receptors at high concentrations (1 mM) as shown in Table 2. Neither of the quisqualate analogs showed any activity at AMPA or kainate (KA) receptors. In summary, one may conclude from this work that the introduction of either a methyl or benzyl group into the a-position of the parent quisqualate structure results in a remarkable change in its biological properties. This structural change leads to the loss of its potent agonist action at both non-NMDA ionotropic glutamate receptors as well as at group I mGluRs, while allowing it to acquire antagonist properties with relative selectivity for group II metabotropic glutamate receptors.l° Acknowledgments. We are indebted in part to Pharmacia-Upjohn and the NIH (grants NS28130 and NS01720) for their support of this research.
PY - 1998/3/3
Y1 - 1998/3/3
N2 - Syntheses of both the α-methyl and benzyl analogs of quisqualic acid are described. Testing of these compounds for their activity at excitatory amino acid receptors revealed a striking change in activity in comparison to quisqualic acid. This structural modification results in the loss of quisqualate's potent agonist action at both non-NMDA ionotropic glutamate receptors as well as at group I mGluRs, while allowing these analogs to acquire antagonist properties with relative selectivity for group II metabotropic glutamate receptors.
AB - Syntheses of both the α-methyl and benzyl analogs of quisqualic acid are described. Testing of these compounds for their activity at excitatory amino acid receptors revealed a striking change in activity in comparison to quisqualic acid. This structural modification results in the loss of quisqualate's potent agonist action at both non-NMDA ionotropic glutamate receptors as well as at group I mGluRs, while allowing these analogs to acquire antagonist properties with relative selectivity for group II metabotropic glutamate receptors.
UR - http://www.scopus.com/inward/record.url?scp=0032478241&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032478241&partnerID=8YFLogxK
U2 - 10.1016/S0960-894X(98)00052-3
DO - 10.1016/S0960-894X(98)00052-3
M3 - Article
C2 - 9871596
AN - SCOPUS:0032478241
VL - 8
SP - 447
EP - 452
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 5
ER -