Exploration of Diazaspiro Cores as Piperazine Bioisosteres in the Development of σ2 Receptor Ligands.
TMEM97
bioisosteres
diazaspiro cores
sigma-2 receptors
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
27 Jul 2022
27 Jul 2022
Historique:
received:
27
06
2022
revised:
19
07
2022
accepted:
21
07
2022
entrez:
28
7
2022
pubmed:
29
7
2022
medline:
30
7
2022
Statut:
epublish
Résumé
A series of σ2R compounds containing benzimidazolone and diazacycloalkane cores was synthesized and evaluated in radioligand binding assays. Replacing the piperazine moiety in a lead compound with diazaspiroalkanes and the fused octahydropyrrolo[3,4-b] pyrrole ring system resulted in a loss in affinity for the σ2R. On the other hand, the bridged 2,5-diazabicyclo[2.2.1]heptane, 1,4-diazepine, and a 3-aminoazetidine analog possessed nanomolar affinities for the σ2R. Computational chemistry studies were also conducted with the recently published crystal structure of the σ2R/TMEM97 and revealed that hydrogen bond interactions with ASP29 and π-stacking interactions with TYR150 were largely responsible for the high binding affinity of small molecules to this protein.
Identifiants
pubmed: 35897835
pii: ijms23158259
doi: 10.3390/ijms23158259
pmc: PMC9332756
pii:
doi:
Substances chimiques
Ligands
0
Receptors, sigma
0
Piperazine
1RTM4PAL0V
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIA NIH HHS
ID : R41 AG052249
Pays : United States
Organisme : NIA NIH HHS
ID : R42 AG052249
Pays : United States
Organisme : NIA NIH HHS
ID : R42AG052249
Pays : United States
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