PNU-22394

Pharmacology

PNU-22394 acts as a potent modulator of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. Its affinities (Ki), activational potencies (), and efficacies () were respectively 19nM and 67.2nM (64%) at the serotonin 5-HT2A receptor, 28.5nM and 71.3nM (13%) at the serotonin 5-HT2B receptor, and 18.8nM and 18.8nM (83%) at the serotonin 5-HT2C receptor. 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. Besides for the serotonin 5-HT2 receptors, PNU-22394 shows very weak affinity for the imidazoline I2 receptor (Ki = 1,030nM).

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

History

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

Analogues

Various analogues of PNU-22394 have also been studied and described.

References

References

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7. (1971). "Appetite suppression and central nervous system stimulation in the rhesus monkey". Psychopharmacologia.
8. (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.
9. (1968). "Annual Reports in Medicinal Chemistry". Elsevier.
10. (June 2025). "Classic Psychedelics in Pain Modulation: Mechanisms, Clinical Evidence, and Future Perspectives". ACS Chemical Neuroscience.
11. (March 2025). "Ibogalogs decrease neuropathic pain in mice through a mechanism involving crosstalk between 5-HT2A and mGlu2 receptors". Biomedicine & Pharmacotherapy.
12. (March 2006). "The potential use of selective 5-HT2C agonists in treating obesity". Expert Opinion on Investigational Drugs.
13. (November 1967). "U-22,394A: a controlled evaluation in chronic schizophrenic patients". Current Therapeutic Research, Clinical and Experimental.
14. (January 1968). "Azepinoindoles. I. Hexahydroazepino[4,5-b]indoles". Journal of Medicinal Chemistry.
15. (November 1968). "Comparison of N,N'-diethyltryptamine and U-22,394A, a new tryptamine derivative". Archives Internationales de Pharmacodynamie et de Therapie.
16. (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.