Sigma-1 agonists as neuroprotectants

Sigma 1 receptors (S1R) are unique non-opioid receptors located at the endoplasmic reticulum (ER)-mitochondrion interface known as the MAM (Mitochondrion Associated endoplasmic reticulum Membrane). They are ubiquitously expressed in the central nervous system, but are also found in peripheral organs including lung, liver, kidney, eye and heart. One S1R subtype was cloned in 1996. It is an integral membrane protein of 223 amino acids with three hydrophobic domains (Figure 1).

Figure 1: Structure of σ1 protein [1]

S1R are chaperones that correct misfolded proteins, stabilize other ER proteins and regulate ER-associated degradation (ERAD). Moreover, S1R localization is dynamic, and S1R are able to translocate from the MAM to the plasma membrane, where they may regulate a variety of functional proteins, including ion channels, receptors and kinases. Thus these receptors are involved in the regulation of numerous neurotransmitter systems [2].

 

In previous work in our laboratory, a series of tetrahydroisoquinoline-hydantoin (tic-hydantoin)–derived compounds were described, with potent affinity for S1R in the nanomolar range, high selectivity toward S2R and low cytotoxicity (IC50 > 100 μM) [3,4].These ligands were evaluated in different pharmacological models, and compound 1 showed high efficiency in a cocaine addiction model [7], ischemia and experimental autoimmune encephalomyelitis [8].

A lot of chemical modulations have been made on this compound (Figure 2) [5,6,9,10]. The project is now dedicated to the replacement of tetrahydroisoquinoline-hydantoin with other cycles or heterocycles to maintain affinity, selectivity and optimize ADME properties.

Figure 2. Compound 1 and Pharmacomodulation

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[2] Su T-P et al. Trends Pharmacol. Science 2010, 31, 557-566
[3] Charton J et al. Bioorg. Med. Chem. Lett. 2005, 15, 4833-4837
[4] Cazenave-Gassiot A et al. Bioorg. Med. Chem. Lett. 2005, 15, 4828-4832
[5] Toussaint M et al. Eur. J. Med. Chem. 2010, 45 (1), 256-263
[6] Toussaint M et al. MedChem. 2010, 6(6), 355-73
[7] Toussaint M et al. Eur. Neuropsychopharmacol. 2009, 19, 504-515
[8] Oxombre B et al. Brit. J. Pharmacol. 2015, 172 (7), 1769-82
[9] Donnier-Maréchal M et al. Eur. J. Med. Chem. 2015, 92, 575-82
[10] Donnier-Maréchal M et al. Eur. J. Med. Chem. 2015, 89, 198-206