Abuse Liability Assessment of Neuroprotectants

Abstract

There has been considerable interest in the potential of N-methyl-D-aspartate (NMDA) receptor antagonists in the treatment of a diverse group of neurological disorders including cerebral ischemia and neurodegeneration. The amino acids L-glutamate and L-aspartate have been shown to possibly mediate excitatory synaptic transmission in the central nervous system (CNS) via selective excitatory amino acid receptors. Competitive and noncompetitive antagonists acting at the NMDA receptors have been shown to possess relevant activity. However, NMDA antagonists can produce a variety of adverse neurobehavioral effects in both animals and humans. These adverse events are particularly pronounced with NMDA antagonists (phencyclidine (PCP), ketamine, and MK-801) that have dissociative anesthetic properties and block NMDA receptor-mediated responses by binding to the cation channel of the NMDA receptor complex. When a new pharmaceutical product demonstrates structural similarity and/or a similar pharmacological profile with a known drug of abuse, the characterization of its abuse potential is needed by the FDA for scientific review. The abuse liability assessment is based upon an evaluation of data on the chemistry, pharmacology (preclinical and clinical), pharmacokinetics, and pharmacodynamic profiles of the drug, and the adverse events/effects reported in clinical trials. The evaluation of the drug's abuse potential is determined relative to pharmacologically similar drugs. This includes determination of the drug's receptor binding efficacy, preclinical pharmacology, reinforcing efficacy, discriminative stimulus effects, dependence-producing potential, pharmacokinetics, and assessment of the clinical efficacy-safety database relative to abuse and clinical abuse liability studies. It has been well established that high-affinity noncompetitive NMDA antagonists have reinforcing efficacy and can serve as discriminative stimuli in operant procedures. In a variety of species in drug discrimination studies, each antagonist is capable of generalizing to the others, and it is believed that these effects may be mediated through the NMDA blockade. The generalization of each substance for another suggests production of common subjective effects in humans.

From PCP to MXE: a comprehensive review of the non‐medical use of dissociative drugs

“…Abuse liability of NMDAR antagonists has been discussed by FDA staff [205] and others. [200] Carrol has reviewed research on abuse liability of PCP and related compounds including pre-clinical animal models such as drug discrimination, self-administration, tolerance, and physical dependence.…”

Non-Invasive Brain Stimulation to Enhance Post-Stroke Recovery

“…Yet, it remains accessible to less than 5–10% of the population since the therapeutic window is restricted to 6 h (Wahlgren et al, 2016 ). In addition, the development of neuroprotective pharmacological treatments to limit the neuronal loss induced by ischemia proved disappointing when translating from experimental studies to clinical studies (Klein et al, 1999 ). The dogma, according to which, any brain injury is irreversible in adults and cannot be repaired has long prevailed both in medical schools and at the bedside.…”

Agmatine reduces balance deficits in a rat model of third trimester binge-like ethanol exposure

“…MK-801 works via channel blockade and demonstrates little receptor subtype specificity. Thus, its wide-ranging actions can produce toxicity, may disrupt learning and memory, and can have abuse/psychotomimetic potential (Grant et al, 1991;Klein, et al, 1999). Although the side effects of MK-801 preclude its use clinically, success in animal models of early ethanol exposure has generated interest in alternate NMDAR antagonists that may be more viable.…”