New and versatile approaches to the synthesis of CPP-related competitive NMDA antagonists. Preliminary structure-activity relationships and pharmacological evaluation

Article abstract of DOI:10.1021/jm00172a037

Fourteen new CPP analogues have been prepared with methyl 1-(phenylmethyl) (±)-1,2-piperazinedicarboxylate 3 as a versatile synthetic intermediate. Derivatives were evaluated as NMDA ligands by their ability to displace [³H]CPP from rat cortical membranes. The binding affinity of various chain lengths and the N⁴-position of the CPP analogues, 5a, 5b, and 9a mimics the binding affinity observed for the acyclic derivatives AP6, AP8, and AP5. Analogue 9a, with a single methylene group in its phosphonate side chain, exhibited diminished affinity for the NMDA receptor when compared to the structurally similar piperidine compound CGS 19755. Replacement of the phosphonic acid moiety with monoionizable acidic groups such as a carboxylase or a phosphinate resulted in a reduction of binding affinity. An aryl spacer between the N⁴-nitrogen and the distal acidic group was detrimental to binding as was alkylation at the N¹-position. Steric bulk, however, was better tolerated when a phenyl group was positioned α to the phosphonate, as seen with analogues 21 and 22.