The NMDA receptor complex (NR) is one of the main targets of the excitatory neurotransmitter glutamic acid. A partial block of the NR by protons even at physiological pH can by removed by the natural polyamines (PAs) spermidine and spermine. Several unbranched diamines as arcaine and 1,12-dodecane-diamine (N12N) seem to block the NR (at least to some extent) via the same mechanism (polyamine inverse agonists). Systematic structural modification led to the discovery of 5-(4-aminobutyl)-2 thiopheneoctanamine (N4T8N), one of the most potent compounds in this family (IC₅₀ 0.2 μM). Via allosteric sites, ifenprodil and zinc increase the sensitivity of the NR to proton inhibition, blocking the NR in apparent competition with stimulating PAs. Here, the recent literature is reviewed on compounds interacting directly or indirectly with PA regulation of the NR.