Sigma-1 ligands: Tic-hydantoin as a key pharmacophore

High‐affinity σ1 protein agonist reduces clinical and pathological signs of experimental autoimmune encephalomyelitis

“…Compound 1(S) was synthesized according to a previously reported protocol (Toussaint et al ., ). BD1047 (N‐[2‐(3,4‐dichlorophenyl)ethyl]‐N‐methyl‐2‐(dimethylamino)ethylamine hydrochloride) was supplied by Tocris (Bristol, UK).…”

“…A synthetic, high‐affinity and selective ligand for the σ1 protein, compound 1(S), contains the tetrahydroisoquinoline‐hydantoin structure, a limited number of free rotation bonds and a very low cytotoxicity providing a high selectivity index (ratio CC 50 /IC 50 ), greater than 50 000 (Cazenave Gassiot et al ., ; Charton et al ., ; Toussaint et al ., ). It also has an agonist profile in cocaine‐induced hyperlocomotion and locomotor sensitization (Toussaint et al ., ).…”

Kinetics and mechanism of racemization of Tic-hydantoins, potent sigma-1 agonists

“…In the literature, the 1 H and 13 C spectra of 1 and 2 in chloroform CDCl 3 are described. 5,6 Herein, the attribution of the 1 H signals was performed in deuterated phosphate buffer/ethanol-75/25 (v/v); the results are displayed in Table 5. Moreover, as illustrated in Figure 7 for compound (S)-1, the deuteration of proton 10a was identified by the integration decrease of the signal at 4 ppm (corresponding to protons 10a, 14 and 14 0 ) and the coupling disappearing.…”

“…Pharmacomodulation of the Tic-hydantoin structure has led to compound 2. 6 Despite the use of the same asymmetric synthesis procedure used for the preparation 0957-4166/$ -see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2011.01.015 of 1 and 3-7, we have previously demonstrated 7 that both enantiomers of 2 were in fact racemic mixtures.…”

Design and synthesis of fused tetrahydroisoquinoline-iminoimidazolines

“…Our group described a series of tetrahydroisoquinoline-hydantoin (Tic-H 1, Figure 1) derived compounds with potent affinity for the sigma-1 receptor in the nanomolar range ensuing various therapeutical in vivo applications. [4][5][6][7][8][9] This heterocycle presents an interesting hydrogen bond acceptor group on the hydantoin cycle and is amenable to various decorations. In this study we proposed to identify a new potential privileged structure and decided to evaluate the consequence of replacing the hydantoin's (1) hydrogen bond acceptor by a hydrogen bond donor group resulting in the guanidine moiety of compound 2 (Figure 1).…”