A series of polyamines based on the high affinity sigma receptor ligand N-[2-(3,4-dichlorophenyl)-ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3) were developed and evaluated for their binding characteristics at sigma-1 and sigma-2 receptor subtypes. The data indicated that a considerable degree of structural variation is possible while still retaining nanomolar affinity at sigma receptors. As the structure of the polyamines was varied, their binding at sigma-1 and sigma-2 subtypes showed quite different and in some cases opposite trends, supporting the belief that these are pharmacologically distinct entities. Polyamines containing two nitrogen atoms showed optimal binding at both sigma-1 and sigma-2 receptor subtypes. Although additional nitrogen atoms resulted in decreased affinity at sigma-1 and sigma-2 subtypes, an increase in selectivity for sigma-2 subtypes was evident; the parent 3 showed greater selectivity for sigma-1 subtypes. Internitrogen spacings had a large effect on binding affinity and subtype selectivity. For example, the difference between N-[3-(1-pyrrolidinyl)propyl]-N'-(3,4-dichlorobenzyl)-N,N'- dimethylethylenediamine (8) [K(i) = 29.9 nM at sigma-1 receptor and 18.3 nM at sigma-2 receptor] to N-[3-(1-pyrrolidinyl)propyl]-N'-(3,4-dichlorobenzyl)- N,N'-dimethylethylenediamine (10) [K(i) = 1.49 nM at sigma-1 receptor and 12.1 nM at sigma-2 receptor] illustrates the importance of internitrogen spacing. Triamines 11 and 13 [Ki(sigma-2)/K(i)(sigma-1) = 0.19 and 0.10, respectively] containing the N-N-N-Ar spacings 3-3-2 and 4-4-2, proved to be the most sigma-2 subtype selective of the 15 polyamines examined in this study. The N-N-N spacings appear to be an important factor in their sigma-2 subtype selectivity. These compounds will serve as templates in the design of still further sigma-2 subtype selective ligands. The pyrrolidine ring (present in most of the polyamines tested in this series) proved to be an important recognition site for sigma receptor binding activity. Furthermore, alkyl substitution also appears to be important since the stripped down polyamines N-[2-(3,4-dichlorophenyl)ethyl]ethylenediamine (15) and N1-[2-(3,4-dichlorophenyl)ethyl]diethylenetriamine (16) exhibited relatively low binding affinity.

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.