Osavampator

Osavampator (developmental code names TAK-653 and NBI-1065845) is an experimental drug being investigated as a treatment for treatment-resistant depression.^[1] It is being developed by Takeda Pharmaceuticals (Millennium Pharmaceuticals, Inc.).^[1][2]

Osavampator

Clinical data
Other names	TAK-653; NBI-1065845; NBI-845
Legal status
Legal status	Investigational
Pharmacokinetic data
Elimination half-life	33.1–47.8 hours
Identifiers
IUPAC name 9-(4-cyclohexyloxyphenyl)-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide
CAS Number	1358751-06-0
PubChem CID	56655833
DrugBank	DB16304
ChemSpider	81367230
UNII	9E3TOE5RIZ
KEGG	D13050
ChEMBL	ChEMBL4594403
Chemical and physical data
Formula	C19H23N3O3S
Molar mass	373.47 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC1=CN2CCS(=O)(=O)N=C2C(=N1)C3=CC=C(C=C3)OC4CCCCC4
InChI InChI=1S/C19H23N3O3S/c1-14-13-22-11-12-26(23,24)21-19(22)18(20-14)15-7-9-17(10-8-15)25-16-5-3-2-4-6-16/h7-10,13,16H,2-6,11-12H2,1H3 Key:PXJBHEHFVQVDDS-UHFFFAOYSA-N

Pharmacology

Osavampator is a selective positive allosteric modulator (PAM) of the AMPA receptor.^[3][4] Osavampator and other AMPA PAMs potentiate the effects of agonists at the main site of the AMPA receptor by slowing the rate of desensitization and internalization of the receptor.^[5]

The terminal half-life of osavampator is 33.1–47.8 hours.^[6]

Research

Depression

There is evidence suggesting that activation of the AMPA receptor, downstream activation of mammalian target of rapamycin (mTOR), and upregulation of brain-derived neurotrophic factor (BDNF) are central to the antidepressant effects of certain NMDA receptor antagonists such as ketamine.^[7] Blockage of the AMPA receptor nullifies the antidepressant actions of ketamine in rodents.^[8] By potentiating the effect of endogenous glutamate at the AMPA receptor, osavampator more directly influences AMPA receptor-mediated transcription.^[5]

The potential use of osavampator as a non-psychotomimetic antidepressant is cited as reason for its investigation.^[3] Initial research found that osavampator, unlike ketamine, did not induce hyperlocomoter responses in rats. However, a later human trial investigating the central nervous system (CNS) stimulatory properties and tolerability of osavampator reported that although the CNS stimulatory properties of the drug were less pronounced than other psychostimulants, osavampator did appear to possess at least some stimulant-like effects.^[4] No severe adverse effects were noted in the trial.^[4]

AMPA receptor agonists are likely not viable for clinical applications as they present a risk of inducing seizures and overexcitation-induced neurotoxicity at doses close to their therapeutic window.^[9][10][11] Osavampator possesses minimal direct AMPA agonist properties.^[9] Osavampator provides a 419-fold safety margin against convulsions relative to therapeutic doses in rats.^[9]