The racemic trans- and cis-isomers of 1-amino-2-phosphonomethyl- cyclobutanecarboxylic acid (5 and 6) and 1-amino-2-phosphonomethyl- cyclopentanecarboxylic acid (7 and 8) were synthesized as extensions of the mGluR4 agonists trans- and cis-1-amino-2-phosphonomethyl-cyclopropanecarboxylic acid (3 and 4). Although the methylene bridge in 3 and 4 allows for retention of affinity toward the mGluR4 receptor, increasing the bridging unit to the ethylene group as in 5 and 6 or to the trimethylene group as in 7 and 8 introduces sufficient steric hindrance to eliminate affinity for the mGluR4 receptor.
Bibliographical noteFunding Information:
This work was supported in part from a grant from NIH (NS35608) and a Development Grant in Drug Design from the Department of Medicinal Chemistry, University of Minnesota. The crystallographic analysis carried out by Neil R Brooks and Victor G. Young, Jr. of the University of Minnesota X-ray Crystallographic Laboratory is gratefully acknowledged. The authors thank Dr. James Monn and Renee Emkey of Eli Lilly and Company for arranging and conducting, respectively, the biological testing.
- Conformational analogues