Nafadotride is a highly potent and competitive dopamine D3 receptor antagonist (D3DR), with efficacy against D2DR and D4DR as well. Nafadotride displayed a high affinity for dopamine D2 and D3 receptors, but a low affinity for doparnine D1 and D4. At dopamine D2 and D3 receptors, the potency was concentrated on the l-enantiomer, which was 7 and 20 times, respectively, more potent than the d-enantiomer. dl-Nafadotride, l-nafadotride and d-nafadotride were 6, 10 and 2 times, respectively, more potent at dopamine D3 than at D2 receptors. As compared to haloperidol, a D 2 receptor preferring antipsychotic, the behavioral profile of nafadotride is characterized by stimulant properties on locomotor activity of rats habituated to their environment occurring at low dosage, i.e. in the range of 1 mg/kg. In contrast, nafadotride exerts typical D 2 receptor blocking responses at much higher dosage: for instance, about 100-fold higher dosages were required to observe extrapyramidal effects like catalepsy.

ADX-47273 is a research pharmaceutical developed by Addex Therapeutics. It is a novel positive allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). ADX-47273 displays antipsychotic, neuromodulatory, and cognition enhancing activities. In vivo, ADX 47273 increases waking and decreases deep sleep behaviors; it also increases late phase long-term potentiation (LTP) and enhances adaptive learning. In other animal models, ADX-47273 decreases amphetamine- and phencyclidine-induced hyperlocomotion and accumbal dopamine levels.

LY2033298 is a selective allosteric modulator for muscarinic acetylcholine M4 receptor. It exerts antipsychotic action in animal models. The compound is able to modulate circadian activity rhythms and morphine-induced conditioned place preference in rats.

PNU-177864 is a selective antagonist of D3 receptor. Compound was considered as a drug candidate for the chronic treatment of schizophrenia, but severe myopathy was found in skeletal muscles of rats during the initial safety evaluation of PNU-177864. Myopathy was associated with phospholipidosis in numerous tissues.

D-alanine is an isomer of non-essential L-amino acid. D isomer is found in the cell walls of bacteria, but not in bacterial proteins. It was discovered, that being an endogenous agonist of the glycine site of the N-methyl-d-aspartate (NMDA) receptor, D-alanine can have beneficial effects on schizophrenia.

Anabasine, a tobacco alkaloid, was used as a biomarker of active tobacco use. Anabasine is a selective alpha7-nicotinic acetylcholine receptor agonist. Anabasine antagonized MK-801-elicited mouse popping behavior, an animal model of schizophrenia.

Myricitrin is a naturally occurring polyphenol hydroxy flavonoid. Myricitrin has a variety of beneficial properties, such as antiviral, antimicrobial, antinociceptive, and anticarcinogenic activities. In particular, myricitrin possesses stronger oxidative resistance and free radical scavenging activity than other flavonol rhamnosides or quercetin. Myricitrin showed antipsychotic-like effects in animal models at doses that did not induce catalepsy or alter locomotor activity, suggesting that myricitrin may be a potential drug treatment for the positive symptoms of schizophrenia.

Piperidine is a normal constituent in mammalian brain. It was shown to affect synaptic mechanism in the CNS, and influence neural mechanisms governing regulation of emotional behavior, sleeping, and extrapyramidal function. In addition, there are enzyme systems within the brain that synthesize and metabolize piperidine, and uptake and storage mechanisms for piperidine are found in the nerve endings. Piperidine, which proved to be a highly effective “antipsychotomimetic” agent in rats, has been reported to bring about substantial improvement in a variety of schizophrenic patients.

2-Phenylaminoadenosine (CV-1808) is an adenosine A2 receptor agonist. CV-1808 is a coronary vasodilator, antihypertensive and antipsychotic following systemic administration in vivo. CV-1808 appeared to be effective for salvaging ischemic myocardium. The effect might be related to improvement of coronary circulation and inhibition of release of vasoactive substances, including TXA2, from the ischemic myocardium. Development of CV-1808 has been discontinued in the United States.

SCH-23390 is a potent and selective antagonist of the D1A and D1B dopamine receptors having Ki of 0.2 and 0.3 nM respectively. The C11 radiolabeled version has proven to be useful as a PET imaging probe in humans for the investigation of a number of neurological conditions including Schizophrenia, Parkinson's Disease, and Huntington's Disease. It should be noted that the non-radiolabeled compound did receive preclinical interest as a potential therapeutic (annotated separately), although such efforts have been discontinued due to side-effects and a lack of therapeutic efficacy.