Sarizotan (also known as EMD-128,130), a chromane derivative that was developed as a selective 5-HT1A receptor agonist and D2 receptor antagonist. Experiments on animal models have shown that the drug effectively suppressed levodopa-induced dyskinesia in primate and rodent models of Parkinson's disease, and tardive dyskinesia in a rodent model. Sarizotan participated in phase II/III clinical trials in the treatment of dyskinesia associated with the dopaminergic treatment of Parkinson's disease. However, further development for this disease was discontinued by Merk, because phase III did not confirm earlier Phase II findings. On July 14, 2015, Newron Pharmaceuticals, research, and development company focused on the novel central nervous system (CNS) and pain therapies, announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to sarizotan for treatment of Rett syndrome. Besides, the drug now is an ongoing clinical trial phase II/III to investigate its the tolerability and efficacy in reducing respiratory abnormalities in Rett Syndrome.

Aplindore (DAB-452) is a small molecule that displays potent dopamine D2 receptor partial agonist activity in in vitro and in vivo assays and is predicted to have antipsychotic efficacy without motor side effects. Aplindore had been in phase II clinical trials for the treatment of Parkinson's disease and restless legs syndrome. Aplindore was generally well tolerated and there were no withdrawals due to adverse events and no serious adverse events.

Zicronapine (formerly known as Lu 31-130), an oral antipsychotic that was studied for the treatment of schizophrenia. The drug was used in a phase III clinical trial.

Fananserin is a potential antipsychotic compound with a high affinity for both D4 and 5-HT2A receptors, and negligible affinity for D2 receptors. Fananserin has been researched for the treatment of schizophrenia. Fananserin was the first selective D4/5-HT2A antagonist to undergo clinical trials for schizophrenia. It has a high affinity for D4 (Ki 2.9 nM) and 5-HT2A (Ki 0.37 nM) receptors and is over 100-fold selective versus H1, a1 adrenergic, 5-HT1A and D2 dopamine receptors. Development of this compound was halted following phase II clinical trials due to lack of efficacy.

Sonepiprazole exhibits highly specific binding to the D4 dopamine receptor with more than 100-fold selectivity for the D4 receptor over other receptors, including dopamine, serotonin, and adrenergic receptors. It is a neutral antagonist at the D4 dopamine receptor and is devoid of dopamine agonist activity. Sonepiprazole selectively induces c-fos expression in the prefrontal cortex and blocks behavioral, biochemical, and genomic effects of repeated amphetamine administration in rats. Sonepiprazole was investigated as an antipsychotic for the treatment of schizophrenia in a placebo-controlled clinical trial, but in contrast to its comparator olanzapine no benefits were found and it was not researched further for this indication.

Ocaperidone [R 79598] is an equipotent antagonist of central dopamine D2 and serotonin2 receptors being investigated as a potential antipsychotic agent. Ocaperidone is a benzisoxazol piperidine antipsychotic primarily binds and with high affinity to 5-HT2 (serotonin) receptors, alpha1 and alpha 2 adrenergic receptors, dopamine D2 receptors and histamine H1 receptors. Ocaperidone is an antagonist primarily at the 5HT and D2 receptors. A proposed mechanism of action is the central D2 receptor blockade which is common to all neuroleptics that are used to treat positive symptoms of schizophrenia.

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).

AstraZeneca R&D Charnwood (formerly Astra Charnwood, a subsidiary of AstraZeneca) was developing sibenadet (Viozan, AR-C68397AA) for the potential treatment of chronic obstructive pulmonary disease and asthma. Sibenadet is a dual D2 dopamine receptor, beta2-adrenoceptor agonist that combines bronchodilator activity with the sensory afferent modulating effects associated with D2-receptor agonism. Development of sibenadet has been discontinued due to disappointing efficacy findings.

Fallypride F-18 is a radiolabeled form of dual dopamine D2/D3 receptor antagonist. It is used as a PET tracer to characterize the distribution and binding potential of striatal and extrastriatal dopamine D2/D3 receptors in animals as well as in normal and diseased human brain.

Mafoprazine is a phenylpiperazine derivative exerting postsynaptic dopamine D2 receptor blocking activity and alpha-adrenergic activity (alpha 1 receptor blocking activity and alpha 2 receptor stimulating activity). In animal models, mafoprazine demonstrated antipsychotic, aggression-inhibiting and cataleptogenic actions.