SYNTHESIS OF N,N'-SUBSTITUTED PIPERAZINE AND HOMOPIPERAZINE DERIVATIVES WITH POLYAMINE-LIKE ACTIONS AT N-METHYL-D-ASPARTATE RECEPTORS

A series of N,N'-substituted piperazine and homopiperazine derivatives have been synthesized with the objective of producing compounds that interact with polyamine modulatory sites on N-methyl-D-aspartate (NMDA ) receptors. These novel compounds exhibited polyamine-like actions, e nhancing [H-3]MK-801 binding to NMDA receptors in rat forebrain membra nes. The potencies of N,N'-bis(2-aminoacetyl)homopiperazine (15), N,N' -bis(N-methyl-4-aminobutyl)piperazine (7), and N,N'-bis(3-aminopropyl) homopiperazine (11) (EC(50) 18.0, 21.3, and 24.4 mu M, respectively) t o enhance [H-3]MK-801 binding were comparable to that of spermine (EC( 50) 5.2 mu M). However, the efficacies of 15, 7, and 11 in this measur e were lower (by similar to 40%, 32%, and 24%, respectively) than sper mine, which may be indicative of partial agonist actions. Like spermin e, the ability of these piperazine and homopiperazine derivatives to e nhance [H-3]MK-801 binding could be inhibited by both a competitive po lyamine antagonist (arcaine) and a specific, noncompetitive polyamine antagonist (conantokin-G). However, unlike endogenous polyamines; high concentrations (up to 1 mM) of these novel polyamine-like compounds d id not inhibit [H-3]MK-801 binding. N,N'-Aminoalkylated and aminoacyla ted piperazine and homopiperazine derivatives may prove useful for stu dying polyamine recognition sites associated with NMDA receptors.