Ensaculin is related to naturally occurring benzopyranones like scoparone. The compound is a potent functional antagonist of excitatory amino acid-induced convulsions and mortality. In receptor-binding studies, Ensaculin showed high affinity to dopaminergic (D2, D3), serotoninergic (5-HT1A, 5-HT7), and adrenergic (A1a, A1b) receptors in the nanomolar range. Ensaculin antagonizes NMDA responses in a voltage-dependent manner. Various studies support the notion that this compound could indeed have a broad range of nootropic properties. Although few patients presented postural hypotension and dizziness after receiving ensaculin in phase I clinical trials, this drug candidate was further discontinued in phase III due to potential side effects.

Dimiracetam is a nootropic drug of the racetam family. Dimiracetam inhibited the NMDA-induced increase of [3H]D-Asp release from hippocampal synaptosomes. The increased potency and longer duration of action of dimiracetam, together with the potential cognition enhancing property makes it a very promising and safe for the treatment of neuropathic pain conditions for which there are very limited therapeutic options. Dimiracetam is in Phase II clinical trials for the treatment of HIV-associated pain and in phase I clinical trials for the treatment of osteoarthritis pain.

AE-37 (ANAVEX2-73, Tetrahydro-N, N-dimethyl-2, 2-diphenyl-3-furanemethanamine) is an orally available drug candidate developed to potentially modify Alzheimer’s disease rather than temporarily address its symptoms. It has a clean Phase 1 data profile and shows a reversal of memory loss (anti-amnesic properties) and neuroprotection in several models of Alzheimer’s disease. This drug is in Phase II trials for Alzheimer's disease, phase I trials for epilepsy, and in preclinical trials for amyotrophic lateral sclerosis, Parkinson's disease, Rett syndrome, stroke. AE-37 may function as a pro-drug for ANAVEX19-144 and acts as a muscarinic receptor and a moderate sigma1 receptor agonist.

N-Methyl-D-aspartic acid is an amino acid derivative acting as a specific agonist at the NMDA receptor, and therefore mimics the action of the neurotransmitter glutamate on that receptor. Unlike glutamate, NMDA only binds to and regulates the NMDA receptor and has no effect on other glutamate receptors (such as those for AMPA and kainate). NMDA receptors are particularly important when they become overactive during withdrawal from alcohol as this causes symptoms such as agitation and, sometimes, epileptiform seizures. NMDA is a water-soluble synthetic substance that is not normally found in biological tissue.

(+)-selfotel ((+)-CGS-19755) is an enantiomer of selfotel, a competitive antagonist at N-methyl-D-aspartate (NMDA)-preferring receptors. The inhibition of NMDA-evoked ACh release from rat striatal slices is stereospecific, with the (+)-enantiomer less potent than the (-)-enantiomer.

1-aminocyclopropanecarboxylic acid (ACPC) is a non-proteinogenic alpha-amino acid consisting of cyclopropane having amino and carboxy substituents both at the 1-position. It has a role as a plant metabolite and a member of ethylene releasers. ACPC is produced endogenously in the tomato and other higher plants as a product of the action of 1-aminocyclopropane-1-carboxylic acid synthase in the biosynthesis of ethylene. It is a monocarboxylic acid and a non-proteinogenic alpha-amino acid. It derives from a cyclopropanecarboxylic acid. ACPC is a partial agonist at the strychnine-insensitive glycine recognition site on the N-methyl-D-aspartate (NMDA) receptor complex in the mammalian central nervous system with preclinical activity in animal models of neuroprotection and psychiatric illnesses. Half-maximal activation by ACPC as a glycine-site agonist was 0.7 to 0.9 microM. Half-maximal inhibition by ACPC was dependent on NMDA concentration. Peak responses to a >100 microM ACPC pulse in the presence of 1 microM glutamate were similar to those of glycine but decayed to a steady-state amplitude below that of glycine. The removal of ACPC initially caused an increase in inward current followed by a subsequent decrease to baseline levels. This suggests that relief of low-affinity antagonism occurs before high-affinity agonist dissociation. ACPC is shown to block convulsions and death produced by NMDA exposure, significantly reducing seizure induction and cell death of NMDA-treated hippocampal neurons.

Midafotel (CPPene; SDZ EAA 494) is a selective competitive antagonist at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. It was originally designed as a potential therapy for excitotoxicity, epilepsy or neuropathic pain. Midafotel had been in phase III clinical trials by Novartis for the treatment of brain injury. However, this research has been discontinued.

Dexoxadrol is a sigma receptor agonist. Dexoxadrol, the D-isomer of dioxodrol, which produces PCP-like behavioural effects and displaces bound [3H]PCP, was a potent blocker of the PCP-sensitive, voltage-gated K+ channel. Dexoxadrol was developed as analgesics for use in humans, however, severe side effects including psychotomimetic effects, unpleasant dreams and aberrations stopped the clinical evaluation of dexoxadrol. Dexoxadrol is a NMDA receptor antagonist, which possesses high affinity to the phencyclidine binding site within the NMDA receptor associated ion channel.