TY - JOUR
T1 - Synthesis, molecular modeling, and biology of the 1-benzyl derivative of APDC - an apparent mGluR6 selective ligand
AU - Tückmantel, Werner
AU - Kozikowski, Alan P.
AU - Wang, Shaomeng
AU - Pshenichkin, Sergey
AU - Wroblewski, Jarda T.
N1 - Funding Information:
Discussion. As is apparent from Table 1, ACPD has little selectivity among the three groups of mGluRs. APDC, on the other hand, shows excellent selectivity for group II receptors, exhibiting an ECs0 of 0.3 laM at rat mGluR2. This compares favorably with the result reported by Schoepp et al. in which they found an ECs0 for inhibition of forskolin-stimulated cAMP formation of 3.5 laM in human mGluR2 expressing cells) 2 The N-benzoyl derivative of APDC, compound 9, is inactive. This result underscores the important role that the basic, non-ring nitrogen atom of APDC plays in receptor recognition. Of particular note is the result found for the 1-benzyl derivative of APDC (7). While exhibiting very weak antagonist activity at group I and II, the compound is most potent and selective as an agonist for mGluR6. Although 7 is less potent than AP4 (ECso = 1 p.M at mGluR6), it is likely to exhibit other important properties, such as better bioavailability due to the presence of the lipophilic benzyl group, that should contribute to its usefulness as a pharmacological research tool (log P = 0.50 versus -2.26 for AP4). The present modeling studies, while somewhat limited by the availability of subtype selective ligands, appear to suggest that the aa conformation of L-glu is relevant to mGluR2 recognition. The modeling studies also suggest that the benzyl group in 1-benzyl-APDC sterically interferes with group I and mGluR2 binding, but is favorable to mGluR6 binding. This information may facilitate the design of other structurally novel mGluR ligands with improved potency and subtype selectivity.~ Acknowledgments. We are indebted to Pharmacia-Upjohn for their support of these studies. JTW also wishes to acknowledge NIH grant NS01720 for a research career development award.
PY - 1997/3/4
Y1 - 1997/3/4
N2 - The synthesis of the 1-benzyl derivative of (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylic acid (1-benzyl-APDC) starting from cis-4-hydroxy-D-proline is disclosed together with a study of the activity of this compound at metabotropic glutamate receptors (mGluRs). The compound was found to display good mGluR6 selectivity, and may thus be a useful pharmacological research tool.
AB - The synthesis of the 1-benzyl derivative of (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylic acid (1-benzyl-APDC) starting from cis-4-hydroxy-D-proline is disclosed together with a study of the activity of this compound at metabotropic glutamate receptors (mGluRs). The compound was found to display good mGluR6 selectivity, and may thus be a useful pharmacological research tool.
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U2 - 10.1016/S0960-894X(97)00068-1
DO - 10.1016/S0960-894X(97)00068-1
M3 - Article
AN - SCOPUS:0031552161
SN - 0960-894X
VL - 7
SP - 601
EP - 606
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 5
ER -