UH-232, or (+)-UH-232, also known as 5-hydroxy-1-methyl-2-(dipropylamino)tetralin methyl ether (5-HMDPTME), is a dopamine and serotonin receptor modulator of the 2-aminotetralin family which was under development for the treatment of schizophrenia but was never marketed. It is taken orally. Contrary to expectations, the drug did not end up producing antipsychotic effects in clinical trials. Instead, it was reported to produce stimulant, hallucinogenic, and psychosis-exacerbating effects.
Use and effects UH-232 has been reported to produce stimulant, hallucinogenic, and psychosis-exacerbating effects in humans. The hallucinogenic effects of UH-232 have been reported to include "perceptual disturbances", "illusions", "aberrations of perception of auditory, visual and tactile stimuli", and "visual hallucinations". Based on preclinical findings, it has been theorized that the hallucinogenic effects of UH-232 may be due to serotonin 5-HT2A receptor agonism and hence that it may be a serotonergic psychedelic.
Interactions
Pharmacology
Pharmacodynamics UH-232 is a dopamine D2 and D3 receptor antagonist or weak partial agonist. It shows about 3- or 4-fold selectivity or higher affinity for the dopamine D3 receptor over the dopamine D2 receptor (Ki = 4.2–11 nM and 15–40 nM, respectively). The drug is an antagonist at dopamine D2Sh autoreceptors on dopaminergic nerve terminals. It also interacts with the dopamine D4 receptor to a much lesser extent (Ki = 48–100 nM). The drug's activational efficacy is 16% at the dopamine D2 receptor, 16 to 40% at the dopamine D3 receptor, and 15% at the dopamine D4 receptor. However, it showed more than 1,000-fold lower activational potency at the dopamine D4 receptor than at the dopamine D2 and D3 receptors. It is said to be unknown whether UH-232 is a functional antagonist or partial agonist of the dopamine receptors in humans. In addition to the dopamine D2 and D3 receptors, UH-232 shows affinity for the dopamine D1 receptor (Ki = 159 nM), serotonin 5-HT2 receptor (Ki = 118 nM), and 5-HT1A receptor (Ki = 144–168 nM). Its affinity for the serotonin 5-HT2 receptor is around 10-fold lower than for the dopamine D2 and D3 receptors. The drug has been reported to increase serotonin 5-HT2 receptor-mediated phosphoinositol turnover in fibroblasts transfected with the rat serotonin 5-HT2A receptor, suggesting that it may act as a serotonin 5-HT2A receptor agonist. Accordingly, UH-232 produced hallucinogenic effects in humans. UH-232 produces hyperlocomotion (a stimulant-like effect) at low doses and mild hypolocomotion at high doses. It also produces weak stereotypies. The stimulant-like effects of UH-232 have been thought to be due to preferential dopamine autoreceptor antagonism and consequent disinhibition of dopamine release. However, they might also be related to postsynaptic D3 receptor antagonism. Another possibility is that serotonin 5-HT2A receptor activation may be involved in its stimulant-like effects. UH-232 produces synergistic and marked hyperlocomotion in combination with a subthreshold dose of the NMDA receptor antagonist dizocilpine (MK-801) in monoamine-depleted rodents, an effect that can be antagonized by dopamine D1 and D2 receptor antagonists and by the serotonin 5-HT2 receptor antagonist ritanserin. UH-232 stimulates prolactin secretion in rodents. It has been found to antagonize the hyperlocomotion or stimulant-like effects of cocaine, dextroamphetamine, and apomorphine in rodents. The drug also antagonized their reinforcing effects in rodents. However, it did not antagonize the interoceptive effects of cocaine in rodent drug discrimination tests. In addition, it was able to partly substitute for cocaine in these tests.
Pharmacokinetics The oral bioavailability of UH-232 is 3.7% and elimination half-life is 2.5 hours in rats.
Chemistry In terms of chemical structure, UH-232 is a substituted 2-aminotetralin, cyclized phenethylamine, and partial ergoline.
Synthesis The chemical synthesis of UH-232 has been described.
Analogues
The N-monopropyl derivative (+)-AJ-76 is an active metabolite of UH-232 and has practically identical effects. Another analogue of UH-232 is UH-242 (5-HMDPT; 5-OH-MDAT). Other analogues of UH-232 include 5-OH-DPAT, 7-OH-DPAT, 8-OH-DPAT, DOM-AT, PNU-99,194, RDS-127, rotigotine, and UH-301, among others. In addition, UH-232 is structurally similar to the cyclized tryptamine and partial ergoline RU-28251 (4,α-methylene-DPT).
History UH-232 was first described in the scientific literature by Arvid Carlsson and colleagues by 1986. It was developed by AstraZeneca. A clinical study of UH-232 for treatment of schizophrenia was published in 1998. It was also evaluated in healthy volunteers, in whom it unexpectedly produced hallucinogenic effects.
Research UH-232 was under development for the treatment of schizophrenia. It reached phase 1 clinical trials for this indication before development was discontinued. The drug did not improve symptoms of schizophrenia in a small trial. Instead, it appeared to exacerbate symptoms, including increasing unusual thought content, anxiety, activation, and hostility. Besides treatment of schizophrenia, UH-232 has been proposed for potential use in the diagnosis of early-stage Parkinson's disease.
See also Substituted 2-aminotetralin Cyclized phenethylamine Partial ergoline List of investigational antipsychotics List of miscellaneous 5-HT2A receptor agonists Robalzotan
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