Neuroprotective derivatives of tacrine that target NMDA receptor and acetyl cholinesterase - Design, synthesis and biological evaluation

Abstract

The complex and multifactorial nature of neuropsychiatric diseases demands multi-target drugs that can intervene with various sub-pathologies underlying disease progression. Targeting the impairments in cholinergic and glutamatergic neurotransmissions with small molecules has been suggested as one of the potential disease-modifying approaches for Alzheimer’s disease (AD). Tacrine, apotent inhibitor of acetylcholinesterase (AChE) is the first FDA approved drug for the treatment of AD. Tacrine is also a low affinity antagonist of N-methyl-D-aspartate receptor (NMDAR). However, tacrine was withdrawn from its clinical use later due to its hepato-toxicity. With an aim to develop novel high affinity multi-target directed ligands (MTDLs) against AChE and NMDAR, with reduced hepatotoxicity, we performed in silico structure-based modifications on tacrine, chemical synthesis of the derivatives and in vitro validation of their activities. Nineteen such derivatives showed inhibition with IC50 values in the range of 18.53±2.09 to 184.09±19.23 nM against AChE and 0.27±0.05 to 38.84±9.64 μM against NMDAR. Some of the selected compounds also protected rat primary cortical neurons from glutamate induced excitotoxicity. Two of the tacrine derived MTDLs, 201 and 208 exhibited in vivo efficacy in rats by protecting against behavioral impairment induced by administration of the excitotoxic agent, monosodium glutamate. Additionally, several of these synthesized compounds also exhibited promising inhibitory activities against butyrylcholinesterase and β-secretase. Given the therapeutic potential of MTDLs in disease-modifying therapy, our studies revealed several promising MTDLs of which 201 appears to be a potential candidate for immediate preclinical and clinical evaluations.

Tacrine Derivatives in Neurological Disorders: Focus on Molecular Mechanisms and Neurotherapeutic Potential

“…It is not known if tacrine and/or its metabolites are excreted in the bile or if they are transported via the enterohepatic system. The clearance of tacrine, however, does not appear to be affected by renal impairment [9,15,21]. [24].…”

“…It was first used in clinical practice to treat anesthetic-induced delirium and to enhance the muscle-relaxing effects of succinylcholine [13]. It was first thought that tacrine would help counteract the respiratory depression caused by morphine; however, it was later revealed that it also acted as an inhibitor of both AChE and butyrlcholine esterase (BChE) [9,14]. In 1993, tacrine became the first medicine to be licensed for the treatment of Alzheimer's disease; however, its hepatotoxicity limited its usage [1].…”

“…Among the pyrano[3,2-e]pyridines and pyrano [2,3b]quinolines groups, the pyrrolyl possessing molecule compound (8) is by far the most effective, with an IC 50 against AChE: 1.7 μM, approximately 10-fold decline in levels of activity in comparison to tacrine. Compound (9) was the most powerful of the [1,8]naphthyridine derivatives, with an IC 50 against AChE: 1.4 μM [26].…”

“…After a while, the tacrine-exposed cells were unable to maintain homeostasis any longer and eventually died. Tacrine promoted ER stress and apoptosis, which were inversely related to the concentration of AChE [9]. By causing ER stress in neurons, other AChEIs (rivastigmine and bis(3)-cognitin) could create the same problem as tacrine.…”

“…A number of investigations have indicated that the memory-enhancing qualities of tacrine are more nuanced than previously thought. It has been shown to target a variety of pathways, including the thenitrinergic, gamma-aminobutyric acid (GABA)ergic, glutamatergic, and AChE pathways [6][7][8][9][10].…”