Nefiracetam

Nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxopyrrolidin-1-yl)acetamide, research code DM-9384) is a synthetic racetam: the 2-(2-oxopyrrolidin-1-yl)acetamide core of piracetam with a 2,6-dimethylphenyl group on the amide nitrogen (PubChem CIDs 71157 and 4843). Daiichi Pharmaceutical researchers described it as a cyclic derivative of GABA (Watabe et al., 1993) and tested it in rat learning models (Sakurai et al., 1989).

Daiichi developed it for the after-effects of cerebrovascular disorders and for Alzheimer-type dementia, then withdrew its Japanese new drug application in 2002 for insufficient efficacy (Crespi, 2002).

PubChem CID 71157 lists the same CAS number and formula, gives the weight as 246.30 g/mol, and is the source of the synonyms and structure.

Published work on nefiracetam falls into six areas. Each summary below states the model used. Cell and animal data come largely from Daiichi and its collaborators, and most human trials found no difference from placebo.

Calcium channels and G proteins

In NG108-15 neuroblastoma-glioma cells, nefiracetam at 1 µM doubled L-type calcium channel currents, and cyclic AMP analogs mimicked the effect. Nefiracetam also promptly reversed the inhibition of N-type currents by Leu-enkephalin, which works through inhibitory Go/Gi proteins, but not inhibition by prostaglandin E1 through stimulatory G proteins. Cells exposed beforehand to pertussis toxin, which inactivates Go/Gi, no longer responded, and the N-type effect was reproduced in Xenopus oocytes expressing N-type channels and delta-opioid receptors (Yoshii et al., 2000). Models: a neuronal cell line and frog oocytes.

Nicotinic receptors and the PKA and PKC pathways

With Torpedo nicotinic receptors expressed in Xenopus oocytes, nefiracetam briefly depressed acetylcholine currents at 0.01 to 0.1 µM through a pertussis toxin-sensitive, PKA-dependent route, and caused a long-lasting enhancement at 1 to 10 µM through calcium-dependent PKC (Nishizaki et al., 1998). In cultured rat cortical neurons it potentiated α4β2-type currents to 200 to 300 percent of control at 1 nM.

There, PKA and PKC inhibitors did not prevent the potentiation, cholera toxin abolished it, and human α4β2 receptors in a human cell line were inhibited instead (Zhao et al., 2001). The signaling route differed between preparations. Models: frog oocytes, rat neurons and a human cell line.

GABAergic findings

Rats given 10 mg/kg by mouth daily for 7 days showed higher GABA turnover and glutamic acid decarboxylase activity in cortex and hippocampus. In cortical slices, 1 and 10 nM raised potassium-evoked GABA release, while binding at GABA-A and benzodiazepine sites was unchanged (Watabe et al., 1993). In cultured rat dorsal root ganglion neurons, 10 µM shifted the GABA concentration-response curve toward lower concentrations but cut the maximal current by about 23 percent; a PKA inhibitor blocked both the transient potentiation and the suppression (Huang et al., 1996). Models: rats, rat brain slices and rat neurons.

Learning and memory models in rodents

In a 1989 Daiichi study, nefiracetam given before training lessened electroconvulsive shock and scopolamine amnesia in a rat passive avoidance task, with bell-shaped response curves, and daily exposure sped acquisition of shuttle-box active avoidance (Sakurai et al., 1989). In mice, the L-type calcium channel blockers nifedipine and flunarizine and the N-type blocker neomycin weakened its reversal of scopolamine-impaired passive avoidance, which the authors linked to high-voltage-activated calcium channels (Yamada et al., 1994).

In rats given a continuous brain infusion of amyloid beta (1-42), 1 to 10 mg/kg by mouth 1 hour before testing reduced deficits in Y-maze, water maze and passive avoidance tasks (Yamada et al., 1999). Models: rats and mice.

Clinical development and trials after stroke

By September 1999 nefiracetam was in US phase II trials for mental symptoms after stroke and for Alzheimer-type dementia. Daiichi repeated a phase III trial in Japan in people with after-effects of cerebral infarction, and insufficient efficacy in that trial led it to withdraw its Japanese new drug application in February 2002 (Crespi, 2002). An NIH phase 2 trial in Alzheimer's disease (NCT00001933) is marked completed in 2002, with no outcome data posted.

In a double-blind trial of 159 people with major depression within 3 months of stroke, nefiracetam did not differ from placebo over time, though the most severely depressed fifth showed a significant effect at the higher of two daily amounts (Robinson et al., 2008).

In 70 people with post-stroke depression and apathy, randomized to placebo or one of two daily amounts, Apathy Scale scores changed significantly more at the higher amount than at the lower amount or with placebo (Robinson et al., 2009). A two-center Australian trial screened 2,514 people with stroke, randomized only 13 people with apathy, and found no difference from placebo at 12 weeks (Starkstein et al., 2016). Model: human clinical studies.

Toxicology in dogs and rats

Daiichi toxicology studies reported organ toxicity at high oral exposure. In male beagle dogs given 180 or 300 mg/kg a day, testicular testosterone fell within 4 hours of a single 300 mg/kg exposure. After 4 weeks, semen quality declined and seminiferous tubules showed moderate to severe atrophy with multinucleated giant cells (Shimomura et al., 2004). Male rats given 1500 mg/kg a day for 4 or 9 weeks developed germ cell loss and tubular atrophy, and their matings produced very few pregnancies (Harada et al., 1995).

Dogs given 300 mg/kg a day developed urinary bladder lesions within a week, and three died in weeks 10 to 11 with renal papillary necrosis (Kashida et al., 1996). Rats and monkeys did not develop the necrosis, which the authors linked to a metabolite that concentrated in the dog renal papilla and suppressed prostaglandin synthesis (Tsuchiya et al., 2003). Models: dogs, rats and monkeys.