Talampanel (TLP) was developed as a noncompetitive (allosteric) antagonist of the AMPA receptor. Talampanel does not act directly on the AMPA receptor, but at an allosteric site referred to as the GYKI receptor. Talampanel is being studied in the treatment of brain tumors and other brain disorders, such as epilepsy, Parkinson disease, amyotrophic lateral sclerosis, dyskinesias, glioblastoma, multiple sclerosis. It is a type of AMPA receptor antagonist. Dizziness has been the most commonly reported adverse event, with some sedation and ataxia, drowsiness and headaches reported at higher doses.

Trepipam is a benzazepine derivative. It is a D1-dopamine antagonist. Trepipam significantly reduced aggression in behaviorally disturbed adolescents and in acute schizophrenics without producing concomitant sedation. Trepipam specifically reduces aggressive and hyperactive behaviors in a wide range of laboratory tests in various species, without producing signs of overt CNS depression or neurological impairment. The drug is effective in reducing many forms of aggression including brain stimulated emotional behavior. Trepipam actually had little effect on gross behavior in mice or rats and only produced ataxia at lethal doses.

Solypertine (WIN-18413-2) is an antiadrenergic drug. Solypertine selectively blocked the conditioned avoidance response in rats. Solypertine potentiated hexobarbitone sleeping time, caused hypothermia and afforded protection from amphetamine toxicity inaggregated mice.

Mergocriptine (2-methyl-a-ergocryptine or CBM36-733) is a synthetic long-acting ergot derivative. It exerts agonistic action at dopamine receptors. Mergocryptine may induce the suppression of striatal dopamine turnover by reducing dopamine release via the stimulation of presynaptic dopaminergic autoreceptors. In animal experiments, it may affect cerebral hemodynamics. Mergocriptine has a protective effect on the brain against ischemia.

Nornicotine is a natural alkaloid produced by plants in the genus Nicotiana and is structurally related to nicotine. Nornicotine is the direct precursor of tobacco-specific nitrosamine N'-nitrosonornicotine, which is a highly potent human carcinogen. Nornicotine is an active nicotine metabolite, which accumulates in brain to pharmacologically relevant concentrations following repeated nicotine administration to rats. Nornicotine stimulated DA release from nucleus accumbens in a nicotinic receptor-mediated manner, further supporting the hypothesis that nornicotine contributes to tobacco dependence. Nornicotine is present in Nicotiana tobaccum in both S(-) and R(+) enantiomeric forms. Nornicotine enantiomeric forms appear to differ in analgesic potency and side effects. Exposure to nornicotine results in additional activation of α7-type receptors, which may be important for effects on cognition and attention. Likewise, the effects of nornicotine on α6-containing receptors may contribute to the reinforcing effects of nicotine, and therefore, is relevant to dependence on tobacco. In contrast to nicotine, nornicotine had relatively low activity on receptors other than those containing α7 or α6 subunits. Yaupon Therapeutics was developing Nornicotine as a once a day oral drug for smoking cessation. However this development was discontinued.

Sibopirdine (EXP921) is a cognition enhancing agent structurally related to linopirdine that was in preclinical development with Bristol-Myers Squibb in the USA as a treatment of Alzheimer's disease. EXP921 was a potential drug candidate for the improvement of cognitive performance in patients with Alzheimer's-type dementia. It has been shown to improve cognitive performance in rodent and primate models of learning and memory. EXP921 was observed to increase the depolarization induced release of acetylcholine, dopamine, and, to a lesser extent, serotonin using slices from the rat cerebral cortex, hippocampus, and caudate nucleus.

Talsaclidine (WAL-2014) is a selective full agonist of M1 muscarinic receptor, having partial agonist activity on the M2 and M3 subtypes (with no in vivo consequences). The general receptor profile of talsaclidine demonstrates a nearly specific interaction with muscarinic receptors, having only weak binding affinity for alpha1- and nicotinic receptors. The drug is being tested in phase III of clinical trials for the treatment of Alzheimer's disease.

LEVOFENFLURAMINE is a levorotatory enantiomer of fenfluramine, a substituted amphetamine which was formerly used to treat obesity. LEVOFENFLURAMINE has dopamine-antagonistic properties and, at high doses, increases dopamine concentrations in rat striatal dialysates. It is essentially inactive to reduce food intake in human subjects.

The selective kappa-opioid receptor agonist spiradoline (U62,066E), an arylacetamide, was synthesized with the intention of creating an analgesic that, while still retaining its analgesic properties, would be devoid of the, mainly mu receptor mediated, side effects such as physical dependence and respiratory depression associated with morphine. The racemate spiradoline was found to be highly selective for the kappa receptor, with a Ki of 8.6 nM in the guinea pig. Examination of the enantiomers of spiradoline, showed the (-)enantiomer to be responsible for the kappa agonist properties. Spiradoline easily penetrates the blood brain barrier, and does not seem to have any significant active metabolites. In preclinical studies, spiradoline has a short duration of action with a peak at around 30 min after administration. The analgesic properties of spiradoline are well documented in mice and rats. Antitussive properties have also been reported in rats. Spiradoline was reported to display effects suggestive of neuroprotective properties in animal models of ischemia. In humans, spiradoline is a potent diuretic. It also produces significant sedation presumably due to its antihistamine properties. Preclinical studies have shown that spiradoline reduces blood pressure and heart rate, and has possible antiarrhythmic properties. Clinical studies did not confirm these findings. Although spiradoline had promising effects in animal tests of analgesia, and a reasonably good safety profile in preliminary studies, it did not replace morphine as an analgesic. The available clinical data suggest that spiradoline produces disturbing adverse effects such as diuresis, sedation, and dysphoria at doses lower than those needed for analgesic effects. Spiradoline was in phase II clinical trials with Pharmacia & Upjohn in Japan and the USA, principally for the treatment of pain. However, the commercial development of spiradoline has been discontinued.

Anisodamine is a naturally occurring atropine derivative that has been isolated, synthesized and characterized by scientists in the People's Republic of China. Anisodamine is a non-specific cholinergic antagonist. Anisodamine has been shown to interact with and disrupt liposome structure which may reflect its effects on cellular membranes. Experimental evidence implicates anisodamine as an anti-oxidant that may protect against free radical-induced cellular damage. Its cardiovascular properties include depression of cardiac conduction and the ability to protect against arrhythmia induced by various agents. Anisodamine is a relatively weak alpha(1) adrenergic antagonist which may explain its vasodilating activity. Its anti-thrombotic activity may be a result of inhibition of thromboxane synthesis. Numerous therapeutic uses of anisodamine have been proposed including treatment of septic shock, various circulatory disorders, organophosphorus (OP) poisoning, migraine, gastric ulcers, gastrointestinal colic, acute glomerular nephritis, eclampsia, respiratory diseases, rheumatoid arthritis, obstructive jaundice, opiate addiction, snake bite and radiation damage protection. The primary therapeutic use of anisodamine has been for the treatment of septic shock. Several mechanisms have been proposed to explain its beneficial effect though most mechanisms are based upon the assumption that anisodamine ultimately acts by an improvement of blood flow in the microcirculation. Preliminary studies suggest another important therapeutic use of anisodamine is for the treatment of OP poisoning. Anisodamine has been employed therapeutically since 1965 in the People’s Republic of China primarily to improve blood flow in circulatory disorders such as septic shock, disseminated intravascular coagulation (DIC) and as an antidote to organophosphate poisoning.