UH-232
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| Other names | UH232; (+)-UH-232; (+)-UH232; (+)-cis-5-Methoxy-1-methyl-2-(dipropylamino)tetralin; 5-HMDPTME; 5-Hydroxy-1-methyl-2-(dipropylamino)tetralin methyl ether |
| Routes of administration | Oral[1] |
| Drug class | Dopamine D2 receptor antagonist; Dopamine D3 receptor weak partial agonist; Serotonin 5-HT2A receptor agonist; Hallucinogen; Serotonergic psychedelic |
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| Bioavailability | 3.7% (rats)[2] |
| Metabolites | AJ-76 |
| Elimination half-life | 2.5 hours (rats)[2] |
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| Chemical and physical data | |
| Formula | C18H29NO |
| Molar mass | 275.436 g·mol−1 |
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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.[3][4][1][5] It is taken orally.[1] Contrary to expectations, the drug did not end up producing antipsychotic effects in clinical trials.[4][1] Instead, it was reported to produce stimulant, hallucinogenic, and psychosis-exacerbating effects.[4][1][5]
Use and effects
[edit]UH-232 has been reported to produce stimulant, hallucinogenic, and psychosis-exacerbating effects in humans.[4][1][5] 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".[4][1][5] 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.[4][6][7][1][5]
Interactions
[edit]Pharmacology
[edit]Pharmacodynamics
[edit]UH-232 is a dopamine D2 and D3 receptor antagonist or weak partial agonist.[8][1] 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).[2][1][9][10][8][11] The drug is an antagonist at dopamine D2Sh autoreceptors on dopaminergic nerve terminals.[12][13][14] It also interacts with the dopamine D4 receptor to a much lesser extent (Ki = 48–100 nM).[2][8] 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.[8][1][15] However, it showed more than 1,000-fold lower activational potency at the dopamine D4 receptor than at the dopamine D2 and D3 receptors.[8] It is said to be unknown whether UH-232 is a functional antagonist or partial agonist of the dopamine receptors in humans.[1]
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).[2][1] Its affinity for the serotonin 5-HT2 receptor is around 10-fold lower than for the dopamine D2 and D3 receptors.[1] 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.[1][5] Accordingly, UH-232 produced hallucinogenic effects in humans.[4][1][5]
UH-232 produces hyperlocomotion (a stimulant-like effect) at low doses and mild hypolocomotion at high doses.[1][16] It also produces weak stereotypies.[12] The stimulant-like effects of UH-232 have been thought to be due to preferential dopamine autoreceptor antagonism and consequent disinhibition of dopamine release.[1][12][17] However, they might also be related to postsynaptic D3 receptor antagonism.[1] Another possibility is that serotonin 5-HT2A receptor activation may be involved in its stimulant-like effects.[1] 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.[1][5][18]
UH-232 stimulates prolactin secretion in rodents.[19] It has been found to antagonize the hyperlocomotion or stimulant-like effects of cocaine, dextroamphetamine, and apomorphine in rodents.[20][21] The drug also antagonized their reinforcing effects in rodents.[21] However, it did not antagonize the interoceptive effects of cocaine in rodent drug discrimination tests.[22] In addition, it was able to partly substitute for cocaine in these tests.[22]
Pharmacokinetics
[edit]The oral bioavailability of UH-232 is 3.7% and elimination half-life is 2.5 hours in rats.[2]
Chemistry
[edit]In terms of chemical structure, UH-232 is a substituted 2-aminotetralin, cyclized phenethylamine, and partial ergoline.[23]
Synthesis
[edit]The chemical synthesis of UH-232 has been described.[24][25][26]
Analogues
[edit]
The N-monopropyl derivative (+)-AJ-76 is an active metabolite of UH-232 and has practically identical effects.[12][19] Another analogue of UH-232 is UH-242 (5-HMDPT; 5-OH-MDAT).[16][27] 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
[edit]UH-232 was first described in the scientific literature by Arvid Carlsson and colleagues by 1986.[16][19][12] It was developed by AstraZeneca.[3] A clinical study of UH-232 for treatment of schizophrenia was published in 1998.[4][1] It was also evaluated in healthy volunteers, in whom it unexpectedly produced hallucinogenic effects.[4][1][5]
Research
[edit]UH-232 was under development for the treatment of schizophrenia.[3][4] It reached phase 1 clinical trials for this indication before development was discontinued.[3][4][1] The drug did not improve symptoms of schizophrenia in a small trial.[4][1] Instead, it appeared to exacerbate symptoms, including increasing unusual thought content, anxiety, activation, and hostility.[4][1] Besides treatment of schizophrenia, UH-232 has been proposed for potential use in the diagnosis of early-stage Parkinson's disease.[28]
See also
[edit]References
[edit]- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Lahti AC, Weiler M, Carlsson A, Tamminga CA (1998). "Effects of the D3 and autoreceptor-preferring dopamine antagonist (+)-UH232 in schizophrenia". Journal of Neural Transmission. 105 (6–7). Vienna: 719–734. doi:10.1007/s007020050091. PMID 9826114. S2CID 31976950.
These behavioral observations are consistent with reports of perceptual disturbances and even visual hallucinations when the drug was administered to normal volunteers (M. Larsson, personal communication). [...] (+)-UH232 has several other lesser affinities for cloned central nervous system system (CNS) receptors: 5HT2 (118nM), 5HT1A (144nM), and D1 (159nM) (R. Lahti, personal communication). [...] Further, (+)-UH232 shows an affinity for the 5HT2 receptor, although with only about 1/10 the potency shown for the D2-family receptors (K. Svensson and R. Lahti, personal communications). [...] In the monoamine-depleted mouse model, (+)-UH232 combined with a subthreshold dose of the selective N-methyl-D-aspartate (NMDA) antagonist MK801 produced a marked locomotor stimulation (Svensson et al., 1991). This response was blocked effectively and specifically by the highly selective 5HT2A antagonist MDL 100,907, supporting the interpretation that (+)-UH232 might possess 5HT2 receptor agonist properties (Carlsson, 1995). Alternatively, in in vitro studies, the Ki of (+)-UH232 at the cloned r5HT2A receptor in the presence and absence of GTP was the same. This provides no evidence for two sites, indicating that at this receptor, (+)-UH232 is an antagonist (R. Lahti, personal communication). On the other hand, (+)-UH232 has been found to increase 5HT2-mediated phosphoinositol turnover in fibroblasts transfected with the rat 5HT2A receptor, again suggesting agonist action (C. Schmidt, personal communication). [...] A similar picture has been observed in studies in human volunteers, in whom the signs of stimulation following treatment with single doses of (+)-UH232 were especially conspicuous (perception disturbances, hallucinations). In the present study on schizophrenic patients, signs of psychostimulation were evident. [...] While this constellation of actions might well account for the behavioral stimulation induced by this agent, one cannot rule out that the 5HT2 receptor stimulation suggested by the animal experiments referred to above has played a role.
- 1 2 3 4 5 6 Haadsma-Svensson SR, Smith MW, Lin CH, Neil Duncan J, Sonesson C, Wikström HK, et al. (1994). "Synthesis and biological activity of C-5 modified derivatives of (+)-AJ76 and (+)-UH232: Increased dopamine D3 receptor preference and improved pharmacokinetic properties". Bioorganic & Medicinal Chemistry Letters. 4 (5): 689–694. doi:10.1016/S0960-894X(01)80181-5.
- 1 2 3 4 "Delving into the Latest Updates on UH-232 with Synapse". Synapse. 16 May 2026. Retrieved 29 July 2026.
- 1 2 3 4 5 6 7 8 9 10 11 12 13 Carlsson ML, Carlsson A, Nilsson M (February 2004). "Schizophrenia: from dopamine to glutamate and back". Current Medicinal Chemistry. 11 (3): 267–277. doi:10.2174/0929867043456034. PMID 14965231.
(+)-UH232 was brought to clinical testing on healthy volunteers as well as schizophrenic patients, though only after single doses. In the former group the drug had some mixed actions with respect to mood and wakefulness. However, a rather striking effect was some abnormalities in perception observed in a number of individuals (illusions with a trend to hallucinations). In some of the schizophrenic patients the psychotic symptoms worsened. These effects may be due to 5-HT2-receptor agonist effects of (+)-UH232 [25]. In spite of this disappointing result it was felt that the pharmacological profile of (+)-UH232 was intriguing and clearly worthy of further exploration.
- 1 2 3 4 5 6 7 8 9 Carlsson ML (1995). "The selective 5-HT2A receptor antagonist MDL 100,907 counteracts the psychomotor stimulation ensuing manipulations with monoaminergic, glutamatergic or muscarinic neurotransmission in the mouse--implications for psychosis". Journal of Neural Transmission. General Section. 100 (3): 225–237. doi:10.1007/BF01276460. PMID 8748668.
Likewise, MK-801, as well as the muscarine receptor antagonist atropine and the α2-adrenoceptor agonist clonidine, were found to interact synergistically with the putative 5-HT2 receptor agonist UH-232 to produce locomotor activation in monoamine-depleted mice. All these responses were effectively blocked by the highly selective 5-HT2A receptor antagonist MDL 100,907. [...] A finding of serendipity in this laboratory was that the selective DA D-3 and autoreceptor preferring antagonists UH-232 and A J-76 interact synergistically with MK-801 in monoamine-depleted mice (Svensson et al., 1991). This was an unexpected finding since these agents were assumed to lack direct agonist effects on postsynaptic receptors (Svensson, 1986). [...] prompted us to try selective 5-HT2 receptor antagonists like ritanserin and MDL 100,907. Our observations with these latter two compounds support the interpretation that UH-232 possesses 5-HT2 receptor agonist properties. [...] This conclusion is further strengthened by results from ligand binding studies carried out at the Marion Merrell Dow Research Institute (C Schmidt, personal communication) and the Upjohn company (K Svensson, personal communication) showing affinity of UH 232 for the 5-HT2 receptor. Moreover UH-232 was found to increase 5-HT2-mediated phosphoinositol turnover in fibroblasts transfected with the rat 5-HTzA receptor (C Schmidt, personal communication). Interestingly, when given to healthy volunteers, UH-232 has been observed to give rise to both behavioral inhibition and stimulation as well as aberrations of perception of auditory, visual and tactile stimuli (M Larsson, personal communication).
- ↑ Strange PG (June 2008). "Antipsychotic drug action: antagonism, inverse agonism or partial agonism". Trends in Pharmacological Sciences. 29 (6): 314–321. doi:10.1016/j.tips.2008.03.009. PMID 18471899.
Other D2/D3 partial agonists that have been tested include UH-232, (-)-3-PPP, aplindore and bifeprunox. In one clinical trial, UH-232 was found to be devoid of antipsychotic activity but the interpretation of the outcome was complicated by hallucinogenic effects that were related to 5-HT2A-receptor agonism of the compound [16].
- ↑ Roth BL, Sheffler DJ, Kroeze WK (April 2004). "Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia". Nature Reviews. Drug Discovery. 3 (4): 353–359. doi:10.1038/nrd1346. PMID 15060530.
Intriguingly, (+)-UH232 actually worsened psychotic symptoms, perhaps via a combination of D3 and 5-HT2A agonism29,because 5-HT2A agonism is known to exacerbate psychosis62. [...] Two potential compounds were subsequently tested: (–)PPP and (+)-UH232 (a D3-preferring agonist with 5-HT2A agonism). [...]
- 1 2 3 4 5 Coldwell MC, Boyfield I, Brown AM, Stemp G, Middlemiss DN (July 1999). "Pharmacological characterization of extracellular acidification rate responses in human D2(long), D3 and D4.4 receptors expressed in Chinese hamster ovary cells". British Journal of Pharmacology. 127 (5): 1135–1144. doi:10.1038/sj.bjp.0702657. PMC 1566129. PMID 10455259.
- ↑ Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC (September 1990). "Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics". Nature. 347 (6289): 146–151. doi:10.1038/347146a0. PMID 1975644.
- ↑ Sokoloff P, Giros B, Martres MP, Andrieux M, Besancon R, Pilon C, et al. (February 1992). "Localization and function of the D3 dopamine receptor". Arzneimittel-Forschung. 42 (2A): 224–230. PMID 1586393.
- ↑ "PDSPKiDatabase". pdsp.unc.edu.
- 1 2 3 4 5 Svensson K, Johansson AM, Magnusson T, Carlsson A (November 1986). "(+)-AJ 76 and (+)-UH 232: central stimulants acting as preferential dopamine autoreceptor antagonists". Naunyn-Schmiedeberg's Archives of Pharmacology. 334 (3): 234–245. doi:10.1007/BF00508777. PMID 2880302.
- ↑ Waters N, Lagerkvist S, Löfberg L, Piercey M, Carlsson A (September 1993). "The dopamine D3 receptor and autoreceptor preferring antagonists (+)-AJ76 and (+)-UH232; a microdialysis study". European Journal of Pharmacology. 242 (2): 151–163. doi:10.1016/0014-2999(93)90075-S. PMID 8253112.
- ↑ Aretha CW, Sinha A, Galloway MP (August 1995). "Dopamine D3-preferring ligands act at synthesis modulating autoreceptors". The Journal of Pharmacology and Experimental Therapeutics. 274 (2): 609–613. PMID 7636720.
- ↑ Griffon N, Pilon C, Schwartz JC, Sokoloff P (August 1995). "The preferential dopamine D3 receptor ligand, (+)-UH232, is a partial agonist". European Journal of Pharmacology. 282 (1–3): R3–4. doi:10.1016/0014-2999(95)00460-3. PMID 7498261.
- 1 2 3 Svensson K, Hjorth S, Clark D, Carlsson A, Wikström H, Andersson B, et al. (1986). "(+)-UH 232 and (+)-UH 242: novel stereoselective dopamine receptor antagonists with preferential action on autoreceptors". Journal of Neural Transmission. 65 (1): 1–27. doi:10.1007/BF01249608. PMID 3083041.
- ↑ Sotnikova TD, Gainetdinov RR, Grekhova TV, Rayevsky KS (March 2001). "Effects of intrastriatal infusion of D2 and D3 dopamine receptor preferring antagonists on dopamine release in rat dorsal striatum (in vivo microdialysis study)". Pharmacological Research. 43 (3): 283–290. doi:10.1006/phrs.2000.0773. PMID 11401421.
- ↑ Svensson A, Carlsson M, Carlsson A (1991). "Synergistic interactions between the NMDA antagonist dizocilpine and the preferential dopamine autoreceptor antagonists (+)-AJ 76 and (+)-UH 232 with regard to locomotor stimulation in monoamine-depleted mice". Journal of Neural Transmission. General Section. 85 (1): 69–77. doi:10.1007/BF01244659. PMID 1867840.
- 1 2 3 Svensson K, Carlsson M, Carlsson A, Hjorth S, Johansson AM, Eriksson E (November 1986). "The putatively selective dopamine autoreceptor antagonists (+)-AJ 76 and (+)-UH 232 stimulate prolactin release in rats". European Journal of Pharmacology. 130 (3): 237–242. doi:10.1016/0014-2999(86)90273-6. PMID 3792447.
- ↑ Piercey MF, Lum JT, Hoffmann WE, Carlsson A, Ljung E, Svensson K (August 1992). "Antagonism of cocaine's pharmacological effects by the stimulant dopaminergic antagonists, (+)-AJ76 and (+)-UH232". Brain Research. 588 (2): 217–222. doi:10.1016/0006-8993(92)91578-3. PMID 1393576. S2CID 44478271.
- 1 2 Kling-Petersen T, Ljung E, Svensson K (October 1994). "The preferential dopamine autoreceptor antagonist (+)-UH232 antagonizes the positive reinforcing effects of cocaine and d-amphetamine in the ICSS paradigm". Pharmacology, Biochemistry, and Behavior. 49 (2): 345–351. doi:10.1016/0091-3057(94)90432-4. PMID 7824548.
- 1 2 Callahan PM, Piercey MF, Cunningham KA (1992). "Effects of the putative dopamine autoreceptor antagonists (+)-AJ 76 and (+)-UH 232 on the discriminative stimulus properties of cocaine". Psychopharmacology. 107 (1). Berl: 73–77. doi:10.1007/BF02244968. PMID 1589564.
- ↑ PubChem. "(1S,2R)-5-methoxy-1-methyl-N,N-dipropyl-1,2,3,4-tetrahydronaphthalen-2-amine". PubChem. Retrieved 29 July 2026.
- ↑ Johansson AM, Arvidsson LE, Hacksell U, Nilsson JL, Svensson K, Carlsson A (April 1987). "Resolved cis- and trans-2-amino-5-methoxy-1-methyltetralins: central dopamine receptor agonists and antagonists". Journal of Medicinal Chemistry. 30 (4): 602–611. doi:10.1021/jm00387a004. PMID 3560156.
- ↑ Reddy NL, Francesconi I, Bellott EM (1999). "A short and efficient asymmetric synthesis of (1S,2R)-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin hydrochloride (UH-232)". Tetrahedron: Asymmetry. 10 (17): 3281–3283. doi:10.1016/S0957-4166(99)00333-X.
- ↑ US 5286747, Arvidsson FL, Carlsson PA, Hacksell UA, Hjorth JS, Johansson AM, Lindberg PL, Nilsson JL, Sanchez D, Wikstrom HV, "1-alkyl-2-aminotetralin derivatives", published 29 September 1989, issued 1994-02-15, assigned to Individual
- ↑ PubChem. "5-Hydroxy-1-methyl-2-(di-n-propylamino)tetralin". PubChem. Retrieved 29 July 2026.
- ↑ Zhou J, Li J, Papaneri AB, Cui G (March 2023). "AJ76 and UH232 as potential agents for diagnosing early-stage Parkinson's disease". Neuropharmacology. 226 109397. doi:10.1016/j.neuropharm.2022.109397. PMC 9901527. PMID 36623805.