Sigma-1 ligands: Tic-hydantoin as a key pharmacophore.
Sigma-1 receptors are involved in numerous pathological dysfunctions and the synthesis of selective ligands is of interest. We identified a fused tetrahydroisoquinoline-hydantoin (Tic-hydantoin) structure with high affinity and selectivity for these receptors. We report here our efforts towards the pharmacomodulation of this substructure, the synthesis of 9 analogs with stereochemistry inversion, opening of isoquinoline ring, removal of isoquinoline nitrogen, replacement of isoquinoline by pyridine, of Tic-hydantoin moiety by quinazolinedione heterocycle. All these analogs provided a loss in the affinity for the sigma-1 receptor. The present work underlines the real importance of the Tic-hydantoin moiety for the obtainment of high affinity ligands.
Toussaint
Marion
M
UMR CNRS 8161-Université Lille Nord de France-Institut Pasteur de Lille, 1 rue du Professeur Calmette, B.P. 447, 59021 Lille cedex, France.
Mousset
Deborah
D
Foulon
Catherine
C
Jacquemard
Ulrich
U
Vaccher
Claude
C
Melnyk
Patricia
P
D000818:Animals; D015195:Drug Design; D006801:Humans; D006827:Hydantoins / Q000737:chemistry* / Q000378:metabolism*; D019169:Jurkat Cells; D008024:Ligands; D009584:Nitrogen / Q000737:chemistry; D011804:Quinolines / Q000737:chemistry; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013237:Stereoisomerism; D000097605:Sigma-1 Receptor
D006827:Hydantoins; D008024:Ligands; D009584:Nitrogen; D011804:Quinolines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C037219:quinoline