Gamma-Carbolines Derivatives As Promising Agents for the Development of Pathogenic Therapy for Proteinopathy

Abstract

Uncontrolled protein aggregation, accompanied by the formation of specific inclusions, is a major component of the pathogenesis of many common neurodegenerative diseases known as proteinopathies. The intermediate products of this aggregation are toxic to neurons and may be lethal. The development strategy of pathogenic therapy for proteinopathy is based on the design of drugs capable of both inhibiting proteinopathy progression and increasing the survival of affected neurons. The results of a decade-long research effort at leading Russian and international laboratories have demonstrated that Dimebon (Latrepirdine), as well as a number of its derivatives from a gamma-carboline group, show a strong neuroprotective effect and can modulate the course of a neurodegenerative process in both in vitro and in vivo model systems. The accumulated data indicate that gamma-carbolines are promising compounds for the development of pathogenic therapy for proteinopathies. KEYWORDS ALS, Dimebon, gamma-carbolines, proteinopathy, transgenic animals. ABBREVIATIONS ALS-amyotrophic lateral sclerosis; FUS-fused in sarcoma; NDD-neurodegenerative disease; TDP-43-transactive response DNA binding protein 43 kDa.

Mitochondria as a promising target for developing novel agents for treating Alzheimer's disease

“…Dimebon successfully passed phase II clinical trials, but, like many other drugs subjected to clinical trials for the treatment of AD, did not show statistically significant efficacy in comparison with placebo 52,53 . Meanwhile, Dimebon is a multitarget agent with a highly promising types of activity: the ability to protect neurons from death, in particular, by decreasing the mitochondrial susceptibility to MPT induction, reduce the development of proteopathy, and stimulate autophagy with simultaneous action on a number of neurotransmitter targets, including acetyl‐ and butyrylcholinesterase inhibition 54–56 . The lead compounds identified among MB and γ‐carboline conjugates combined the types of activity promising for anti‐Alzheimer's drugs inherent in the two pharmacophores: they behaved as acetyl‐ and butyrylcholinesterase inhibitors, antioxidants, and microtubule stabilizers and were able to activate the mRC, including the capacity for alternative electron transfer in the mitochondrial electron transport chain, thus compensating for the inhibition of complex I.…”

In a search for efficient treatment for amyotrophic lateral sclerosis: Old drugs for new approaches

“…Example of such drug is Dimebon (latrepirdine; Figure S7), an approved antihistamine drug that has demonstrated some promise in Phase II of clinical trials for mild-to-moderate AD 240,241 and other gamma-carbolines. [242][243][244] Although not tested so far, these compounds seem to be promising candidates for ALS clinical trials because they were shown to efficiently ameliorate pathological aggregation of TDP-43 and other ALS-related aggregation-prone proteins in several in vitro and in vivo systems. [244][245][246][247][248][249][250] Similarly, future studies in ALS models might reveal other "old drugs" or their derivates that deserve to be further tested in clinical trials.…”

“…The answer to this question is a definite “yes,” there are still a number of drugs with proven or suggested mechanisms of action that make them good candidates for testing as potential disease‐modifying or at least slowing disease progression in ALS. Example of such drug is Dimebon (latrepirdine; Figure S7), an approved antihistamine drug that has demonstrated some promise in Phase II of clinical trials for mild‐to‐moderate AD 240,241 and other gamma‐carbolines 242–244 . Although not tested so far, these compounds seem to be promising candidates for ALS clinical trials because they were shown to efficiently ameliorate pathological aggregation of TDP‐43 and other ALS‐related aggregation‐prone proteins in several in vitro and in vivo systems 244–250 .…”

A bioisostere of Dimebon/Latrepirdine delays the onset and slows the progression of pathology in FUS transgenic mice

“…In the last decade, gamma‐carbolines have attracted attention as potential neuroprotectors in the nervous system affected by neurodegenerative processes 5–14 . Their neuroprotective activity can be explained by a combination of multiple mechanisms of action described for these compounds 11,15–28 .…”