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
CompTox Dashboard (EPA)
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

<span class="mw-page-title-main">Ampakine</span> Subgroup of AMPA receptor positive allosteric modulators

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

CX717 is an ampakine compound created by Christopher Marrs and Gary Rogers in 1996 at Cortex Pharmaceuticals. It affects the neurotransmitter glutamate, with trials showing the drug improves cognitive functioning and memory.

<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

CX-614 is an ampakine drug developed by Cortex Pharmaceuticals. It has been investigated for its effect on AMPA receptors.

<span class="mw-page-title-main">IDRA-21</span> Chemical compound

IDRA-21 is a positive allosteric modulator of the AMPA receptor and a benzothiadiazine derivative. It is a chiral molecule, with (+)-IDRA-21 being the active form.

<span class="mw-page-title-main">LY-503430</span> Chemical compound

LY-503430 is an AMPA receptor positive allosteric modulator developed by Eli Lilly.

<span class="mw-page-title-main">PEPA (drug)</span> Chemical compound

PEPA is a sulfonamide AMPA receptor positive allosteric modulator, which is up to 100 times more potent than aniracetam in vitro. It produces memory-enhancing effects in rats when administered intravenously.

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

LY-404187 is an AMPA receptor positive allosteric modulator which was developed by Eli Lilly and Company. It is a member of the biarylpropylsulfonamide class of AMPA receptor potentiators.

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

Pregnenolone sulfate is an endogenous excitatory neurosteroid that is synthesized from pregnenolone. It is known to have cognitive and memory-enhancing, antidepressant, anxiogenic, and proconvulsant effects.

<span class="mw-page-title-main">S-18986</span> Chemical compound

S-18986 is a positive allosteric modulator of the AMPA receptor related to cyclothiazide. It has nootropic and neuroprotective effects in animal studies, and induces both production of BDNF and AMPA-mediated release of noradrenaline and acetylcholine in the hippocampus and frontal cortex of the brain.

<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.

<span class="mw-page-title-main">ALTO-100</span> BDNF-modulating drug for depression and PTSD

ALTO-100, previously known as NSI-189, is a drug described as a hippocampal neurogenesis stimulant and indirect brain-derived neurotrophic factor (BDNF) modulator which is under development for the treatment of major depressive disorder (MDD), bipolar depression, and post-traumatic stress disorder (PTSD). There has also been interest in ALTO-100 for possible treatment of cognitive impairment and neurodegeneration. It is taken by mouth.

<span class="mw-page-title-main">ANA-12</span> Chemical compound

ANA-12 is a selective, small-molecule non-competitive antagonist of TrkB, the main receptor of brain-derived neurotrophic factor (BDNF). ANA-12 was originally discovered and developed by Cazorla M. and colleagues at Université Paris and Inserm in 2011. The compound crosses the blood-brain-barrier and exerts central TrkB blockade, producing effects as early as 30 minutes and as long as 6 hours following intraperitoneal injection in mice. It blocks the neurotrophic actions of BDNF without compromising neuron survival.

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

Pesampator is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which was under development by Pfizer for the treatment of cognitive symptoms in schizophrenia. In March 2018, the development of the drug was transferred over from Pfizer to Biogen. 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. In July 2022, Biogen discontinued the development of pesampator for cognitive symptoms in schizophrenia due to ineffectiveness.

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

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>

AMPA receptor positive allosteric modulators are positive allosteric modulators (PAMs) of the AMPA receptor (AMPR), a type of ionotropic glutamate receptor which mediates most fast synaptic neurotransmission in the central nervous system.

A GABAA receptor negative allosteric modulator is a negative allosteric modulator (NAM), or inhibitor, of the GABAA receptor, a ligand-gated ion channel of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). They are closely related and similar to GABAA receptor antagonists. The effects of GABAA receptor NAMs are functionally the opposite of those of GABAA receptor positive allosteric modulators (PAMs) like the benzodiazepines, barbiturates, and ethanol (alcohol). Non-selective GABAA receptor NAMs can produce a variety of effects including convulsions, neurotoxicity, and anxiety, among others.

<span class="mw-page-title-main">GL-II-73</span> Benzodiazepine drug

GL-II-73 (GL-ii-073) is a benzodiazepine derivative related in chemical structure to compounds such as midazolam and adinazolam. It is described as an α5 preferring positive allosteric modulator of the benzodiazepine site of GABAA receptors, with weaker activity at α2 and α3 and no significant affinity for the α1 subtype. In animal tests it was found to produce effects consistent with antidepressant, anxiolytic and nootropic actions.

<span class="mw-page-title-main">Osavampator</span> Experimental antidepressant

Osavampator is an experimental drug being investigated as a treatment for treatment-resistant depression. It is being developed by Takeda Pharmaceuticals.

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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.