Design and Synthesis of New Acyl Urea Analogs as Potential σ1R Ligands.
Molecules
; 28(5)2023 Mar 02.
Article
en En
| MEDLINE
| ID: mdl-36903567
ABSTRACT
In search of synthetically accessible open-ring analogs of PD144418 or 5-(1-propyl-1,2,5,6-tetrahydropyridin-3-yl)-3-(p-tolyl)isoxazole, a highly potent sigma-1 receptor (σ1R) ligand, we herein report the design and synthesis of sixteen arylated acyl urea derivatives. Design aspects included modeling the target compounds for drug-likeness, docking at σ1R crystal structure 5HK1, and contrasting the lower energy molecular conformers with that of the receptor-embedded PD144418-a molecule we opined that our compounds could mimic pharmacologically. Synthesis of our acyl urea target compounds was achieved in two facile steps which involved first generating the N-(phenoxycarbonyl) benzamide intermediate and then coupling it with the appropriate amines weakly to strongly nucleophilic amines. Two potential leads (compounds 10 and 12, with respective in vitro σ1R binding affinities of 2.18 and 9.54 µM) emerged from this series. These leads will undergo further structure optimization with the ultimate goal of developing novel σ1R ligands for testing in neurodegeneration models of Alzheimer's disease (AD).
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Receptores sigma
Idioma:
En
Revista:
Molecules
Asunto de la revista:
BIOLOGIA
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos