Aniracetam

Aniracetam is 1-(4-methoxybenzoyl)-2-pyrrolidinone. Its research code is Ro 13-5057. It is a synthetic racetam. A 2010 review places it among the piracetam-like drugs (Malykh and Sadaie, 2010). A 1982 rodent study called it a new pyrrolidinone derivative. It countered memory deficits caused in the lab (Cumin et al., 1982). Cell studies show it acts as a positive allosteric modulator of AMPA-type glutamate receptors (Ito et al., 1990).

It has been used clinically for behavioral and psychological symptoms of dementia after stroke and in Alzheimer's disease (Nakamura, 2002).

So are the format and storage. PubChem CID 2196 lists the same CAS number, formula and weight. It is the source of the synonyms and structure.

Published work on aniracetam falls into five areas. Each summary below states the model used. Mechanism and behavior data come from cells, brain tissue and rodents. The few human studies have mixed findings.

Aniracetam and AMPA receptors

One model was Xenopus oocytes expressing rat brain mRNA. There, aniracetam reversibly potentiated responses at quisqualate-type (AMPA) receptors. This was seen above 0.1 mM. It did not change kainate, NMDA or GABA responses. It also enhanced CA1 synaptic potentials in rat hippocampal slices (Ito et al., 1990). Patch-clamp recordings in hippocampal slices showed that it strongly reduces desensitization. This is the closing of channels while glutamate is still bound.

The compound also prolongs fast synaptic currents (Isaacson and Nicoll, 1991). Cocrystal structures of the GluR2 ligand-binding domain place it where two subunits meet. It sits beside the hinge of the glutamate-binding clamshell. Mutating that site disrupted its effect. Deactivation is channel closing after glutamate leaves. The authors propose that it slows deactivation by holding the clamshell closed (Jin et al., 2005). Models: oocytes, rat hippocampal slices and receptor crystals.

Metabolites and pharmacokinetics

In rats, aniracetam and its metabolite N-anisoyl-GABA cleared quickly from plasma. But 2-pyrrolidinone persisted. Oral bioavailability was 11.4 and 8.6 percent at 50 and 100 mg/kg. Most of the compound became N-anisoyl-GABA, p-anisic acid and 2-pyrrolidinone (Ogiso et al., 1998). After intravenous delivery, brain-to-plasma exposure ratios were 53 to 55 percent for 2-pyrrolidinone. For aniracetam, they were 2.4 to 3.2 percent.

N-anisoyl-GABA was not detected in brain (Ogiso et al., 2000). Another study used stroke-prone spontaneously hypertensive rats. N-anisoyl-GABA and p-anisic acid were perfused into their brain regions. After a delay, they raised acetylcholine release. Aniracetam itself did not (Nakamura and Shirane, 1999). So the metabolites may play a role in its effects (Nakamura, 2002). Model: rats.

Memory and anxiety models in rodents

In the 1982 study, aniracetam was given by mouth at 10 to 100 mg/kg. It prevented or reversed deficits in rats and mice. Some deficits were caused by hypercapnia, scopolamine or electroconvulsive shock. Others were caused by chloramphenicol or cycloheximide. The effects were mostly bell-shaped. Piracetam was active in six of nine tests. It was about one-tenth as potent (Cumin et al., 1982). In mice, 10 to 100 mg/kg raised social interaction.

It also had anti-anxiety effects in the elevated plus maze and conditioned fear stress tests. Haloperidol blocked the social interaction effect. Metabolites such as p-anisic acid had the same effects (Nakamura and Kurasawa, 2001). Healthy adult C57BL/6J mice were given 50 mg/kg by mouth daily. However, they did not differ from controls in the water maze, fear conditioning or rotarod tests. Nor did they differ in the open field, elevated plus maze or marble burying (Elston et al., 2014). Models: rats and mice.

Human studies in cognitive impairment

A randomized, double-blind trial studied 44 people with Alzheimer-type dementia. They received aniracetam or placebo for 3 months. Memory and other test scores rose in both groups. Clinical ratings did not differ. Four people on aniracetam and one on placebo stopped because of confusion (Sourander et al., 1987). A 6-month randomized, double-blind, placebo-controlled multicenter trial studied 109 older adults. They had mild to moderate cognitive impairment and probable Alzheimer's disease. The trial reported a significant difference from placebo.

The placebo group showed steady decline (Senin et al., 1991). An open-label study in Greece followed 276 people with cognitive disorders. They were given no drug, aniracetam, cholinesterase inhibitors or both. Scores in the aniracetam group held steady over 12 months. In milder dementia, these scores exceeded those of the cholinesterase inhibitor group on cognition at 6 months. There was no blinding or placebo (Koliaki et al., 2012). Model: human clinical studies.