Tulrampator

Last updated
Tulrampator
Tulrampator skeletal.svg
Clinical data
Other namesS-47445; CX-1632
Identifiers
  • 8-cyclopropyl-3-[2-(3-fluorophenyl)ethyl]-7H-[1,3]oxazino[6,5-g][1,2,3]benzotriazine-4,9-dione
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
Formula C20H17FN4O3
Molar mass 380.379 g·mol−1
3D model (JSmol)
  • C1CC1N2COC3=C(C2=O)C=C4C(=C3)C(=O)N(N=N4)CCC5=CC(=CC=C5)F
  • InChI=1S/C20H17FN4O3/c21-13-3-1-2-12(8-13)6-7-25-20(27)15-10-18-16(9-17(15)22-23-25)19(26)24(11-28-18)14-4-5-14/h1-3,8-10,14H,4-7,11H2
  • Key:JHCFQXNWYDLBOG-UHFFFAOYSA-N

Tulrampator (developmental code names S-47445, CX-1632) is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which is under development by RespireRx Pharmaceuticals (formerly Cortex Pharmaceuticals) and Servier for the treatment of major depressive disorder (as an adjunct), Alzheimer's disease, dementia, and mild cognitive impairment. [1] [2] [3] [4] Tulrampator was in phase II clinical trial for depression, but failed to show superiority over placebo. [5] There are also phase II clinical trials for Alzheimer's disease and phase I trials for dementia and mild cognitive impairment. [2]

Contents

Tulrampator is a "high-impact" AMPAR potentiator, [6] unlike "low-impact" AMPAR potentiators like CX-516 and its congener farampator (CX-691, ORG-24448), and is able to elicit more robust increases in AMPAR activation. [7] In animals, high-impact AMPAR potentiators enhance cognition and memory at low doses, but produce motor coordination disruptions, convulsions, and neurotoxicity at higher doses. [8] Tulrampator itself has been found in animals to enhance cognition and memory, to produce antidepressant-, antianhedonic-, and anxiolytic-like effects, and to have neurotrophic and neuroplasticity-promoting activities. [3] [4] Moreover, it has been found to increase levels of brain-derived neurotrophic factor (BDNF) in the hippocampus and to stimulate hippocampal neurogenesis. [3] [9]

The rapidly-acting antidepressant effects of the NMDA receptor antagonist ketamine appear to be mediated through indirect/downstream activation of AMPARs. [3] This is evidenced by the fact that its antidepressant-like effects in animals are blocked by the AMPAR antagonist NBQX. [3] As such, tulrampator may be a rapid-acting antidepressant similarly to ketamine but without its dissociative/hallucinogenic and certain other adverse effects (e.g., urotoxicity). [3]

See also

Related Research Articles

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Ampakines or AMPAkines are a subgroup of AMPA receptor positive allosteric modulators with a benzamide or closely related chemical structure. They are also known as "CX compounds". Ampakines take their name from the AMPA receptor (AMPAR), a type of ionotropic glutamate receptor with which the ampakines interact and act as positive allosteric modulators (PAMs) of. Although all ampakines are AMPAR PAMs, not all AMPAR PAMs are ampakines.

<span class="mw-page-title-main">CX717</span> Ampakine

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<span class="mw-page-title-main">Farampator</span> Chemical compound

Farampator is an ampakine drug. It was developed by Cortex Pharmaceuticals, and licensed to Organon BioSciences for commercial development. Following the purchase of Organon by Schering-Plough in 2007, the development license to farampator was transferred. The development of farampator was eventually terminated, reportedly due to concerns about cardiac toxicity.

<span class="mw-page-title-main">CX614</span> Chemical compound

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<span class="mw-page-title-main">LY-404187</span> Chemical compound

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<span class="mw-page-title-main">ORG-26576</span> Ampakine

ORG-26576 is an ampakine originally developed by Cortex Pharmaceuticals and then licensed to Organon International for development. In animal studies it has been shown to effectively potentiate AMPA receptor function, leading to increased BDNF release and enhanced neuronal differentiation and survival, as well as producing nootropic effects in standardised assays. Development as an antidepressant has been halted due to a failed Phase II trial for major depressive disorder.

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Pesampator is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which is under development by Pfizer for the treatment of cognitive symptoms in schizophrenia. It was also under development for the treatment of age-related sensorineural hearing loss, but development for this indication was terminated due to insufficient effectiveness. As of July 2018, pesampator is in phase II clinical trials for cognitive symptoms in schizophrenia.

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Mibampator is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which was under development by Eli Lilly for the treatment of agitation/aggression in Alzheimer's disease but was never marketed. It reached phase II clinical trials prior to the discontinuation of its development.

<span class="mw-page-title-main">AMPA receptor positive allosteric modulator</span>

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References

  1. ↑ "Tulrampatorum" (PDF). WHO Drug Information. 30 (4): 684. 2016-12-19. Retrieved 2017-08-31.[ dead link ]
  2. 1 2 "S 47445". AdisInsight. Retrieved 2017-08-31.
  3. 1 2 3 4 5 6 Mendez-David I, Guilloux JP, Papp M, Tritschler L, Mocaer E, Gardier AM, Bretin S, David DJ (2017). "S 47445 Produces Antidepressant- and Anxiolytic-Like Effects through Neurogenesis Dependent and Independent Mechanisms". Front Pharmacol. 8: 462. doi: 10.3389/fphar.2017.00462 . PMC   5515821 . PMID   28769796.
  4. 1 2 Giralt A, Gómez-Climent MÁ, Alcalá R, Bretin S, Bertrand D, María Delgado-García J, Pérez-Navarro E, Alberch J, Gruart A (2017). "The AMPA receptor positive allosteric modulator S 47445 rescues in vivo CA3-CA1 long-term potentiation and structural synaptic changes in old mice". Neuropharmacology. 123: 395–409. doi: 10.1016/j.neuropharm.2017.06.009 . hdl: 2445/160592 . PMID   28603025.
  5. ↑ "Synopsis" (PDF).
  6. ↑ "Patent US9700596 - Locally released growth factors to mediate motor recovery after stroke - Google Patents". google.com. Retrieved 2017-08-31.
  7. ↑ Roberts BM, Holden DE, Shaffer CL, Seymour PA, Menniti FS, Schmidt CJ, Williams GV, Castner SA (2010). "Prevention of ketamine-induced working memory impairments by AMPA potentiators in a nonhuman primate model of cognitive dysfunction". Behav. Brain Res. 212 (1): 41–8. doi:10.1016/j.bbr.2010.03.039. PMID   20347881. S2CID   9432930.
  8. ↑ Ranganathan M, DeMartinis N, Huguenel B, Gaudreault F, Bednar MM, Shaffer CL, Gupta S, Cahill J, Sherif MA, Mancuso J, Zumpano L, D'Souza DC (2017). "Attenuation of ketamine-induced impairment in verbal learning and memory in healthy volunteers by the AMPA receptor potentiator PF-04958242". Mol. Psychiatry. 22 (11): 1633–1640. doi:10.1038/mp.2017.6. PMID   28242871. S2CID   3691566.
  9. ↑ Calabrese F, Savino E, Mocaer E, Bretin S, Racagni G, Riva MA (2017). "Upregulation of neurotrophins by S 47445, a novel positive allosteric modulator of AMPA receptors in aged rats" (PDF). Pharmacol. Res. 121: 59–69. doi: 10.1016/j.phrs.2017.04.019 . PMID   28442348.
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