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, enhancing [3H]MK-801 binding to NMDA receptors in rat forebrain membranes. 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) (EC50 18.0, 21.3, and 24.4 microM, respectively) to enhance [3H]MK-801 binding were comparable to that of spermine (EC50 5.2 microM). However, the efficacies of 15, 7, and 11 in this measure were lower (by approximately 40%, 32%, and 24%, respectively) than spermine, which may be indicative of partial agonist actions. Like spermine, the ability of these piperazine and homopiperazine derivatives to enhance [3H]MK-801 binding could be inhibited by both a competitive polyamine 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 did not inhibit [3H]MK-801 binding. N,N'-Aminoalkylated and aminoacylated piperazine and homopiperazine derivatives may prove useful for studying polyamine recognition sites associated with NMDA receptors.
Zhou
L M
LM
Laboratories of Neuroscience and Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0008, USA.
He
X S
XS
Li
G
G
de Costa
B R
BR
Skolnick
P
P
D000818:Animals; D001645:Biguanides / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011073:Polyamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D013096:Spermine / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001645:Biguanides; D010879:Piperazines; D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; D013096:Spermine; C006624:arcaine