The compound LSL60101 improved cognitive deficit and biomarkers related to Alzheimer’s disease in studies carried out with mice. The work is described in a paper1 detailing the synthesis of a new family of compounds with high affinity and selectivity for imidazoline I2 receptors, altered in the brain of patients with Alzheimer’s.

The synthesis pathway of compounds is efficient and affordable. It would allow different structural modifications to access a range of compounds of pharmaceutical interest.

Apart from fighting the formation of amyloid-beta plaques or neurofibrillary tangles, acting on the neuroinflammation mechanisms could be a suitable therapeutic strategy to stop the progression of such a complex disease like Alzheimer’s,

said professor Carmen Escolano, from the University of Barcelona, who co-led the research team.

I2-IR Receptor Ligand

The new family of I2-IR receptor ligands is formed by compounds with different structural features. In particular, the interaction of a representative compound — LSL60101 or garsevil — with the I2 imidazoline receptors improves cognitive deficit in murine models with neurodegeneration and Alzheimer’s.

This compound, described for the first time in 19952 as a specific I2-IR receptor ligand, is known for its properties in preclinical studies of pharmacokinetics, metabolism and toxicity, and presents a high affinity and selectivity regarding these receptors in the human brain.

The actual physiological function of the I2-IR receptors is currently unknown.

However, researchers know these are altered in some neurodegenerative diseases such as Alzheimer’s or Parkinson’s. Moreover, the scientific bibliography features studies with ligands of these receptors as markers of the progress of Alzheimer’s disease.

LSL60101 Versus Donepezil

The effects of LSL60101 in laboratory animals were shown to be more beneficial than those from donepezil, one of the most commercialized drugs for Alzheimer’s treatments in the murine models.

The new compound created changes in oxidative stress markers and in neuroinflammation makers, one of the main dysfunctions present in most of the neurodegenerative diseases. In particular, LSL60101 reduced the number of amyloid-beta plaques and the levels of this altered protein in the brain of the treated animals. Parallelly, it reduced the phosphorylation of the tau protein, another important biomarker in the progression of the diseases,

said co-leader Professor Mercè Pallàs.

The results could be explained with the several action mechanisms of LSL60101 and donepezil. Donepezil increases the levels of acetylcholine — a neurotransmitter related to memory and cognitive skills — because it inhibits acetylcholinesterase, the enzyme in charge of its degradation.

Also, LSL60101 is described as a I2 imidazoline receptor ligand, which have increased in the brain of people with dementia. Everything points to the fact that the interaction of this drug with its receptor is involved in the generation of proinflammatory molecules that would increase the ongoing neuroinflammation in the disease.

It follows that I2 ligands would contribute to reduce the inflammation and thus, would slow the progression of the disease.

Synergistic Effect

Both compounds were efficient in the recovery of the cognitive damage, but one of the objectives of the research study was to find whether the combination could improve the success of the treatment.

The results show that the SL60101-donepezil combined therapy is more efficient in some biomarkers of the disease. Therefore, it is possible that, with the combination of the suitable dose, we could reach an additive or even synergic effect,

the researchers noted.

Further research is needed to focus on the relation between I2 imidazoline receptors and Alhzeimer’s and other diseases

  1. Sergio Rodriguez-Arévalo, Andrea Bagán, Christian Griñán-Ferré, Foteini Vasilopoulou, Mercè Pallàs, Iria Brocos-Mosquera, Luis F. Callado, M. Isabel Loza, Antón L. Martínez, José Brea, Belén Pérez, Elies Molins, Steven De Jonghe, Dirk Daelemans, Milica Radan, Teodora Djikic, Katarina Nikolic, Elena Hernández-Hernández, M. Julia García-Fuster, Jesús A. García-Sevilla, Carmen Escolano. Benzofuranyl-2-imidazoles as imidazoline I2 receptor ligands for Alzheimer’s disease. European Journal of Medicinal Chemistry, Volume 222, 2021, 113540, ISSN 0223-5234 ↩︎

  2. Regina Alemany, Gabriel Olmos, Pablo V. Escribá, Angel Menargues, Rossend Obach, Jesús A. García-Sevilla. LSL 60101, a selective ligand for imidazoline I2 receptors, on glial fibrillary acidic protein concentration. European Journal of Pharmacology, Volume 280, Issue 2, 1995, Pages 205-210, ISSN 0014-2999 ↩︎

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