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PNU-22394

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PNU-22394
Clinical data
Other namesPNU22394; PNU-22394A; PNU22394A; U-22394A; U22394A
Routes of
administration		Oral
Drug classSerotonin 5-HT2C receptor agonist; Non-hallucinogenic serotonin 5-HT2A receptor agonist; Serotonin 5-HT2B receptor weak partial agonist or antagonist
Identifiers
  • 6-methyl-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC13H16N2
Molar mass200.285 g·mol−1
3D model (JSmol)
  • C3CNCCc2c3c1ccccc1n2C
  • InChI=1S/C13H16N2/c1-15-12-5-3-2-4-10(12)11-6-8-14-9-7-13(11)15/h2-5,14H,6-9H2,1H3 ☒N
  • Key:ZBXDOQWPGBISAR-UHFFFAOYSA-N ☒N
  (verify)

PNU-22394, or PNU-22394A, also known as U-22394A, as well as 6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole, is a serotonin 5-HT2 receptor agonist of the ibogalog family which was studied as an appetite suppressant and antipsychotic but was never marketed.[1][2][3][4] As an ibogalog, PNU-22394 is a cyclized tryptamine and a simplified ibogaine analogue.[5][6]

Pharmacology

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PNU-22394 acts as a potent modulator of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors.[2] Its affinities (Ki), activational potencies (EC50Tooltip half-maximal effective concentration), and efficacies (EmaxTooltip maximal efficacy) were respectively 19 nM and 67.2 nM (64%) at the serotonin 5-HT2A receptor, 28.5 nM and 71.3 nM (13%) at the serotonin 5-HT2B receptor, and 18.8 nM and 18.8 nM (83%) at the serotonin 5-HT2C receptor.[7][2] Hence, it is a near-full agonist of the serotonin 5-HT2C receptor, a moderate-efficacy partial agonist of the serotonin 5-HT2A receptor, and a very weak partial agonist or antagonist of the serotonin 5-HT2B receptor.[7][2] Besides for the serotonin 5-HT2 receptors, PNU-22394 shows very weak affinity for the imidazoline I2 receptor (Ki = 1,030 nM).[8]

PNU-22394 produces anorectic effects and weight loss in both animals and humans[1][3][4][9] as well as pro-cognitive-like effects in animals.[10] The anorectic effects of PNU-22394 in animals can be blocked by the selective serotonin 5-HT2C receptor antagonist SB-242084.[1] PNU-22394 produced side effects in humans including headache, anxiety, nausea, and vomiting, but with rapid tolerance to these side effects that developed within 4 days.[1][2] Despite its activity as a potent serotonin 5-HT2A receptor agonist, PNU-22394 did not produce hallucinogenic effects in humans.[2] Other effects of PNU-22394 in animals included serotonergic tryptamine-like effects, antiaggressive effects, inhibition of conditioned avoidance, and hypothermia,[6][11][12] as well as analgesic effects.[13][14]

History

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PNU-22394 was first described in the scientific literature by 1967.[7][15][12][5] It was originally evaluated by Upjohn in people with schizophrenia in the 1960s.[7][1][15] It showed no antipsychotic effects, but did unexpectedly produce weight loss in most of the patients.[7][6] Subsequently, in the 2000s, PNU-22394 was studied as an appetite suppressant and weight loss medication.[1]

Analogues

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Various analogues of PNU-22394 have also been studied and described.[1][12][16]

See also

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References

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  1. ^ a b c d e f g Bishop MJ, Nilsson BM (2003). "New 5-HT2C receptor agonists". Expert Opinion on Therapeutic Patents. 13 (11): 1691–1705. doi:10.1517/13543776.13.11.1691. ISSN 1354-3776. However, much supporting data have been generated using available [5-HT2C agonists], such as m-chlorophenylpiperazine (m-CPP, compound 2), U-22394A (now known as PNU-22394A, compound 3), Ro 60-0175 (compound 4), ORG-12962 (compound 5), nordexfenfluramine (compound 6) and MK-212 (compound 7) 111,181. These compounds lack high selectivity for the 5-HT2C receptor versus the other 5-HT receptors, especially the other 5-HT2 receptor subtypes, and therefore the resulting pharmacological outcomes should be assigned to 5-HT2C receptor activation with appropriate caution. [...] It is also evident that hypophagia induced by m-CPP, nordexfenfluramine or PNU-22394A in wild-type rodents may be prevented by administration of the selective 5-HT2C receptor antagonist SB-242084 119-21,231. [...] Although not originally aimed at obesity, an Upjohn clinical trial with the non-selective 5-HT2C receptor agonist PNU-22394A (3) resulted in weight loss [22,23]. [...] 3.4 Azepine and diazepnes: In the 1960s, Upjohn evaluated indolylazepine U-22394A (compound 3) in chronic schizophrenic patients and they also described weight loss with this compound [22]. It was patented as an anorectic agent > 30 years ago [163,164]. Compound 3, now known as PNU-22394, was recently described as a potent 5-HT2A/5-HT2C agonist (5-HT2A: Ki = 19 [64% functional response of 5-HT]; 5-HT2B: Ki = 28.5 nM [13%]; 5-HT2C: Ki = 18.8 nM [83%]) [23]. Pharmacia & Upjohn has also described closely related tetracyclic azepinoindoles, such as compound 43 (Figure 6) [165]. [...] Historically, a number of compounds with limited selectivity for 5-HT2C have been tested in clinical trials for various indications, such as m-CPP (2), PNU-22394A (3), ORG-12962 (5) and MK-212 (7) [22,23,31,32,85].
  2. ^ a b c d e f Fitzgerald LW, Ennis MD (2002). "Chapter 3: 5-HT2C receptor modulators: Progress in development of new CNS medicines". Annual Reports in Medicinal Chemistry. Vol. 37. Elsevier. pp. 21–30. doi:10.1016/s0065-7743(02)37004-0. ISBN 978-0-12-040537-4. The closely related azepinoindole 11 (PNU-22394) has been described as a 5-HT2C agonist (Ki = 18.8 nM, 83% efficacy) that has recently been reported to decrease feeding in rats and produce a weight loss in humans (68). Although dose-related clinical side effects observed included headache, anxiety, nausea, and vomiting, these effects were dramatically reduced following four days of dosing. No hallucinations were observed despite the fact that 11 is also a potent, high efficacy 5-HT2A agonist (5-HT2A Ki = 19 nM, 64% efficacy). Compound 11 also has excellent affinity at 5-HT2B receptors (Ki = 28.5 nM).
  3. ^ a b McCall RB, Franklin SR, Hyslop DK, Knauer CS, Chio CL, Haber CL, et al. (2001). "PNU-22394, a 5-HT2C receptor agonist, reduced feeding in rodents and produces weight loss in humans" (Online). Soc Neurosci Abstr. 27 (309.2). Presentation Number 309.2. Convention Center Exhibit Hall, Poster Board TT-45, San Diego, CA: Society for Neuroscience Abstracts. Retrieved 18 July 2014.{{cite journal}}: CS1 maint: location (link)
  4. ^ a b Garfield AS, Heisler LK (January 2009). "Pharmacological targeting of the serotonergic system for the treatment of obesity". The Journal of Physiology. 587 (1): 49–60. doi:10.1113/jphysiol.2008.164152. PMC 2670022. PMID 19029184.
  5. ^ a b Tang AH, Uhlinger BJ, Schroeder LA (November 1968). "Comparison of N,N'-diethyltryptamine and U-22,394A, a new tryptamine derivative". Archives Internationales de Pharmacodynamie et de Therapie. 176 (1): 74–85. PMID 5709792.
  6. ^ a b c Efange SM, Mash DC, Khare AB, Ouyang Q (November 1998). "Modified ibogaine fragments: synthesis and preliminary pharmacological characterization of 3-ethyl-5-phenyl-1,2,3,4,5, 6-hexahydroazepino[4,5-b]benzothiophenes". Journal of Medicinal Chemistry. 41 (23): 4486–4491. doi:10.1021/jm980156y. PMID 9804688. Despite its apparent complexity, the skeleton of ibogaine can be broken down into a number of easily identifiable fragments. [...] However, for the current study we chose a third fragment represented by 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (5). [...] A review of the literature showed that 5 and its derivatives had been developed as conformationally restricted tryptamine analogues.24 In rats, some derivatives of 5 were found to elicit many of the symptoms associated with tryptamine. One of these compounds, 6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (6, U-22,394A), was found to antagonize aggressive behavior in fighting mice, block conditioned avoidance, and induce hypothermia and anorexigenic behavior in rodents.24 However, the compound was devoid of neuroleptic activity when tested in humans.25
  7. ^ a b c d e Smith BM, Thomsen WJ, Grottick AJ (March 2006). "The potential use of selective 5-HT2C agonists in treating obesity". Expert Opinion on Investigational Drugs. 15 (3): 257–266. doi:10.1517/13543784.15.3.257. PMID 16503763. In the 1960s, Upjohn explored a series of azepineindoles [43] that were considered to have therapeutic potential for the treatment of mental diseases. These compounds were considered to have potential antipsychotic activity in humans based on results from fighting mouse, dish and pit avoidance tests and nicotine antagonism. These compounds were additionally anorectic and decreased both body temperature and locomotor activity. U-22,394A 40 mg/day for 9 weeks was compared with chlorpromazine in a controlled, double-blind study of 24 chronic schizophrenic male patients [44]. U-22,394A had no effect on various ratings of schizophrenia, but a side effect was reported in 11 out of 12 treated patients with an average weight loss of 3.18 kg (range: 1.36 – 7.26 kg) compared with 2.54 kg of average weight gain for chlorpromazine-treated patients. The authors concluded that 'the possible anorexigenic effect of this compound observed at 40 mg/day, perhaps merit further study, particularly in light of the absence of significant side effects at this dosage level.' In 2001, this compound was reported to be a nonselective 5-HT2C agonist (Table 1) [45]. [...] Table 1. Screening data for selected 5-HT2C agonists. [...]
  8. ^ Glennon RA, Grella B, Tyacke RJ, Lau A, Westaway J, Hudson AL (February 2004). "Binding of beta-carbolines at imidazoline I2 receptors: a structure-affinity investigation". Bioorganic & Medicinal Chemistry Letters. 14 (4): 999–1002. doi:10.1016/j.bmcl.2003.11.078. PMID 15013009.
  9. ^ Tang AH, Kirch JD (1971). "Appetite suppression and central nervous system stimulation in the rhesus monkey". Psychopharmacologia. 21 (2): 139–146. doi:10.1007/BF00572271. PMID 4998869.
  10. ^ Jensen AA, Plath N, Pedersen MH, Isberg V, Krall J, Wellendorph P, et al. (February 2013). "Design, synthesis, and pharmacological characterization of N- and O-substituted 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol analogues: novel 5-HT(2A)/5-HT(2C) receptor agonists with pro-cognitive properties". Journal of Medicinal Chemistry. 56 (3): 1211–1227. CiteSeerX 10.1.1.691.154. doi:10.1021/jm301656h. PMID 23301527.
  11. ^ Pachter IJ, Rubin AA (1968). "Chapter I. Antipsychotic and Anti-anxiety Agents". Annual Reports in Medicinal Chemistry. Vol. 3. Elsevier. pp. 1–13. doi:10.1016/s0065-7743(08)61305-6. ISBN 978-0-12-040503-9.
  12. ^ a b c Hester JB, Tang AH, Keasling HH, Veldkamp W (January 1968). "Azepinoindoles. I. Hexahydroazepino[4,5-b]indoles". Journal of Medicinal Chemistry. 11 (1): 101–106. doi:10.1021/jm00307a023. PMID 5637151.
  13. ^ Czopek A, Jończyk J, Fryc M, Kluzik D, Zagórska A (June 2025). "Classic Psychedelics in Pain Modulation: Mechanisms, Clinical Evidence, and Future Perspectives". ACS Chemical Neuroscience. 16 (12): 2163–2177. doi:10.1021/acschemneuro.5c00152. PMC 12183689. PMID 40474592.
  14. ^ Arias HR, Micheli L, Jensen AA, Galant S, Vandermoere F, Venturi D, et al. (March 2025). "Ibogalogs decrease neuropathic pain in mice through a mechanism involving crosstalk between 5-HT2A and mGlu2 receptors". Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 184: 117887. doi:10.1016/j.biopha.2025.117887. PMID 39938347.
  15. ^ a b Gallant DM, Bishop MP, Bishop G, O'Meallie L (November 1967). "U-22,394A: a controlled evaluation in chronic schizophrenic patients". Current Therapeutic Research, Clinical and Experimental. 9 (11): 579–581. PMID 4965508.
  16. ^ Ennis MD, Hoffman RL, Ghazal NB, Olson RM, Knauer CS, Chio CL, et al. (July 2003). "2,3,4,5-tetrahydro- and 2,3,4,5,11,11a-hexahydro-1H-[1,4]diazepino[1,7-a]indoles: new templates for 5-HT(2C) agonists". Bioorganic & Medicinal Chemistry Letters. 13 (14): 2369–2372. doi:10.1016/s0960-894x(03)00403-7. PMID 12824036.
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