PNU-22394
| Clinical data | |
|---|---|
| Other names | PNU22394; PNU-22394A; PNU22394A; U-22394A; U22394A |
| Routes of administration | Oral |
| Drug class | Serotonin 5-HT2C receptor agonist; Non-hallucinogenic serotonin 5-HT2A receptor agonist; Serotonin 5-HT2B receptor weak partial agonist or antagonist |
| Identifiers | |
IUPAC name
| |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| UNII | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| Chemical and physical data | |
| Formula | C13H16N2 |
| Molar mass | 200.285 g·mol−1 |
| 3D model (JSmol) | |
SMILES
| |
InChI
| |
| (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]
- ^ 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].
- ^ 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).
- ^ 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) - ^ 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.
- ^ Cite error: The named reference
Tang_1968was invoked but never defined (see the help page). - ^ 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