Dexanabinol is the synthetic cannabinoid. It is inactive as a cannabimimetic, but exhibits pharmacological properties characteristic of an N-methyl-D-aspartate (NMDA)-receptor antagonist. It blocks NMDA-receptors stereospecifically by interacting with a site close to, but distinct from, that of uncompetitive NMDA-receptor antagonists and from the recognition sites of glutamate, glycine, and polyamines. This agent also scavenges peroxy radicals and protects neurons from the damages of reactive oxygen species. Furthermore, dexanabinol inhibits the activity of nuclear factor kappa B (NF-kB), thereby preventing the expression of NF-kB target genes, such as tumor necrosis factor alpha, cytokines and inducible nitric oxide synthase. Dexanabinol is a potent cerebroprotective agent, with a therapeutic window of about 4 h. Dexanabinol is safe, but is not efficacious in the treatment of traumatic brain injury. It was introduced into clinical trials for breast cancer and advanced solid tumors.

CX 516, a compound synthesized by Cortex Pharmaceuticals using Ampakine® technology licensed from the University of California, was in clinical investigations for the treatment of Alzheimer's disease, schizophrenia, fragile X syndrome and autism, and sleep disorders, however, development of this drug candidate has been discontinued. CX 516 had an extremely short halflife in humans, very low potency and failed to show any benefits in phase II studies. The compound did have a good safety profile, reducing concerns about the toxicity of excess glutamate. Cortex subsequently terminated clinical development of CX 516.

Flindokalner (BMS 204352; MaxiPost™) is a neuroprotective agent with potential in the treatment of stroke developed by Bristol-Myers Squibb. Flindokalner is a potent and effective opener of two important subtypes of neuronal potassium channels, the calcium-activated, big-conductance potassium channels (K(Ca) channels) and voltage-dependent, non-inactivating potassium channels known as KCNQ channels. Flindokalner significantly reduced cortical infarct volume in a animal models of stroke. Flindokalner failed to show superior efficacy in acute stroke patients compared to placebo in a Phase III study.

Vanoxerine, also known as GBR-12909, is a piperazine derivative exhibiting potent selective inhibition of sodium-dependent dopamine reuptake transporters. Vanoxerine has been in clinical trials for Parkinsonism, depression and cocaine addiction but lacked efficacy. Vanoxerine has also been observed as a potent blocker of the following channels: cardiac hERG/IKr potassium channel, Calcium channel, voltage-dependent, L type, alpha 1C subunit (also known as Cav1.2) and voltage-gated sodium channel Nav 1.5. Vanoxerine was studied as a potential treatment for atrial fibrillation. However, phase III clinical trials for this condition were terminated because of cardiac safety concerns. Research also indicates that vanoxerine may have additional mechanisms of action including antagonist action at nicotinic acetylcholine receptors (nAChRs).

Licostinel (ACEA 1021) is a potent competitive antagonist at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. The robust efficacy of glycine/NMDA antagonists, such as ACEA 1021, in animal model of brain ischemia, together with good safety profile in animal models and in clinical trials, suggested that this class of NMDA antagonists should have good chance of success in the clinic as neuroprotectants. The clinical trial of ACEA 1021 for stroke was discontinued, mainly due to low solubility and lack of metabolism of the drug that led to the observation of crystals in the urine of some of the patients. In vivo ACEA 1021 reduced the rate of propagation of cortical spreading depression, an effect consistent with blockade of NMDA receptors. ACEA 1021 also decreased audiogenic myoclonus in resuscitated rats following cardiac arrest, and the minimum alveolar concentration for halothane, effects which suggest a reduction of excitatory amino acid neurotransmission. ACEA 1021 crosses the blood-brain barrier and blocks the pathophysiologic consequences of NMDA receptor overstimulation. It was neuroprotective with a favorable therapeutic window in models of transient and permanent cerebral ischemia, epilepsy and pain.

Tisocromide exerts antihypoxic and antidepressant action. The details regarding mechanism of action and use are not available.

Etiracetam is a nootropic agent. (-)-(S) enantiomer of etiracetam levetiracetam (Keppra®) is used for the treatment of epilepsy.

CPI-1189 is a synthetic benzamide with antioxidant properties that blocks tumor necrosis factor-alpha (TNFalpha) effects in animal models. It has neuroprotective properties in model systems for HIV-associated neurotoxicity and thus is a candidate for neuroprotective therapy in humans with HIV-associated CNS disease. CPI-1189 was at the phase II stage of clinical development for the treatment of dementia associated with Parkinson's disease and AIDS Dementia Complex, however, development has been discontinued.

Eritoran (E-5564) is a synthetic lipid A analog that has been designed to antagonize the effects of lipopolysaccharide (LPS) and has been found to do this by interacting with Toll-like receptor 4, the cell surface receptor for LPS. Preclinical in vitro and in vivo studies of eritoran tetrasodium indicate it can limit excessive inflammatory mediator release associated with LPS and improve survival in sepsis models. Clinically, eritoran was being investigated for the treatment of severe sepsis, septic shock, and other endotoxin-mediated indications. Eritoran development has been discontinued.

Nifenalol is the beta-receptor antagonist. It has optical isomers. The racemic mixture and the levo-isomer are active in antagonizing beta-receptors, but the dextro-isomer is inactive. The levo-isomer seems to be about twice as active in blocking beta-receptors as the racemate. Nifenalol is virtually devoid of local anesthetic properties in contrast to procaine, propranolol, and butidrine. Nifenalol exacerbated the fighting behavior in male mice by foot-shock. Nifenalol has been studied in patients with coronary artery disease. It afforded the coronary patient good protection against angina and ischemic changes in the EKG. It was further noted that nifenalol had no antiarrhythmic action and that it was devoid of evident side effects. Nifenalol possessed weak action against tremorine and oxotremorine induced tremor.