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.

GR 103691 is an effective and selective receptor antagonist of the D3DR (dopamine D3 receptor). GR 103691 was shown to have 100-fold higher selectivity for D3DR (dopamine D3 receptor) over the D2DR (dopamine D2 receptor) and D4DR (dopamine D4 receptor) sites. GR 103,691 is functionally active in vivo and will inhibit the hyperactivity response induced by intra-VTA (ventral tegmental area) injection of muscimol in rats.

LY-165163 is a partial agonist of serotonin receptors 5-HT1A and 5-HT1D. It exhibits marked activity at both pre- and postsynaptic dopaminergic D2 (D3 and D1) receptors. LY-165163 caused a significant and dose-dependent hypothermia in rats. As a 5-HT1D receptor agonist, LY-165163 was proposed for the ocular pain treatment.

Pergolide is a long-acting dopamine agonist approved in 1982 for the treatment of Parkinson’s Disease. It is an ergot derivative that acts on the dopamine D2 and D3, alpha2- and alpha1-adrenergic, and 5-hydroxytryptamine (5-HT) receptors. It was indicated as adjunct therapy with levodopa/carbidopa in the symptomatic treatment of parkinsonian syndrome. It was later found that pergolide increased the risk of cardiac valvulopathy. The drug was withdrawn from the US market in March 2007 and from the Canadian market in August 2007. Pergolide stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D1 and D5 subreceptors and are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D2, D3 and D4 subreceptors and has been associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D2 and D3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D2- and D3-receptors. It also exhibits agonist activity on dopamine D4, D1, and D5, 5-hydroxytryptamine (5-HT)1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, α2A-, α2B-, α2C-, α1A-, α1B-, and α1D-adrenergic receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion. Pergolide also causes transient increases in somatotropin (growth hormone) secretion and decreases in luteinizing hormone (LH) concentrations. Pergolide is not available for use by humans in the United States, but approved for veterinary use; it was used in various other countries for the treatment of various conditions including Parkinson's disease, hyperprolactinemia, and restless leg syndrome. Pergolide in Europe was indicated for Parkinson's disease only when other dopaminergic agonist treatments had failed, and treatment had to be initiated by a neurologist. The label warned against using doses of more than 5mg a day, whether alone or in combination with levodopa. However the marketing of this drug finally stopped in France in May 2011 and sales elsewhere in Europe ceased eventually.

Domperidone is a peripherally selective D2 receptor antagonist. It acts as an antiemetic and a prokinetic agent through its effects on the chemoreceptor trigger zone and motor function of the stomach and small intestine. Domperidone was not approved in USA due to risks of cardiac arrhythmias, cardiac arrest, and sudden death, but is available in other countries. However, FDA allows access to Domperidone through an expanded access investigational new drug application (IND) to patients with gastroesophageal reflux disease with upper GI symptoms, gastroparesis, and chronic constipation. As an “off-label” use, domperidone is prescribed to breastfeeding women to enhance their milk production.

Blonanserin is an antagonist of dopamine and serotonin receptors developed for the treatment of schizophrenia. Blonanserin was approved in Japan and Korea, but was never marketed in the USA.