F-17475
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| Drug class | NMDA receptor antagonist; Analgesic; Dissociative; Hallucinogen |
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| Formula | C15H22N2O |
| Molar mass | 246.354 g·mol−1 |
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F-17475 is an NMDA receptor antagonist described as an analgesic and putative dissociative hallucinogen which was under development for the treatment of postoperative pain but was never marketed.[1]
The drug shows similar affinity for the NMDA receptor as ketamine (Ki = 0.74 and 1.05 μM, respectively).[1] It shows analgesic effects in rodents, with about twice the potency of ketamine, and potentiates morphine-induced analgesia.[1] F-17475 substitutes for ketamine in rodent drug discrimination tests, suggesting that it may have dissociative hallucinogen effects in humans.[1] However, F-17475 showed a greater margin of analgesic to dissociative-like effects than ketamine in rodents.[1]
F-17475 was first described in the patent literature by 2012, developed by researchers at Pierre Fabre. The m-chloro derivative is slightly more potent, up to 10x stronger than ketamine, but had a less favorable side effect profile in animal tests.[2]
References
[edit]- ^ a b c d e Mila, M. (2015). "Society for Neuroscience - 45th Annual Meeting. Chicago, Illinois, USA - October 17-21, 2015: F-17475 IS SAFER AND MORE POTENT THAN KETAMINE IN POSTOPERATIVE PAIN". Drugs of the Future. 40 (11): 781–788 (782–782). doi:10.1358/dof.2015.040.11.2407741.
Ronan Depoortere from Pierre Fabre presented preclinical data on F-17475, a glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist. When binding to the NMDA receptors in rats, F-17475 showed a slightly higher affinity than ketamine (Ki = 0.74 and 1.05 µM, respectively). The compound was slightly more potent at blocking NMDA current in rat and human receptors and it dissociated from hNMDA receptors faster. It was also more potent at blocking NMDA current in human native than transfected receptors. In the rat Brennan model of postoperative pain, i.v. administration of F-17475 dose-dependently reduced spontaneous flinching of the injured paw. The compound was as efficacious, but twice as potent, as ketamine against postoperative pain. Additionally, the compound permitted morphine sparing of 50 to 75%, shifting in a dose-dependent manner the morphine analgesic curve to the left in the same model; it was twice as potent as ketamine in 1-hour postsurgery pain (although not presurgery). F-17475 potentiated the analgesic efficacy of morphine at doses 1.25 mg/kg i.v. 1 hour preoperatively; a strong tendency to potentiate was seen at 2.5 mg/kg given 1 hour postsurgery. In relation to abuse liability, while ketamine generalized at doses 4-fold below the analgesic dose and lever pressing disruption occurred at doses 2-fold higher, F-17475 generalized to the ketamine cue at doses 4- to 8-fold above analgesic ones, and disrupted lever pressing at doses 10- to 20-fold higher. Finally, the compound appeared to be much better tolerated than ketamine, with a ratio between doses active in Brennan's model, and those producing signs in the Irwin test, being 20- to 40-fold higher for F-17475 than for ketamine. F-17475 could substitute ketamine for peri- and postoperative pain relief or prevention.
- ^ Vacher B, Blanc E, Depoortere R. Aminocyclobutane derivatives, method for preparing same and the use thereof as drugs. US 9469601
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