New serotonin 5-HT(1A) receptor agonists with neuroprotective effect against ischemic cell damage.
We report the synthesis of new compounds 4-35 based on structural modifications of different moieties of previously described lead UCM-2550. The new nonpiperazine derivatives, representing second-generation agonists, were assessed for binding affinity, selectivity, and functional activity at the 5-HT(1A) receptor (5-HT(1A)R). Computational β(2)-based homology models of the ligand-receptor complexes were used to explain the observed structure-affinity relationships. Selected candidates were also evaluated for their potential in vitro and in vivo neuroprotective properties. Interestingly, compound 26 (2-{6-[(3,4-dihydro-2H-chromen-2-ylmethyl)amino]hexyl}tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione) has been characterized as a high-affinity and potent 5-HT(1A)R agonist (K(i) = 5.9 nM, EC(50) = 21.8 nM) and exhibits neuroprotective effect in neurotoxicity assays in primary cell cultures from rat hippocampus and in the MCAO model of focal cerebral ischemia in rats.
Departamento de Química Orgánica I, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
Isabel
I
Marco
Margarita
M
Valhondo
Mar
M
Martín-Fontecha
Henar
H
Vázquez-Villa
Joaquín
J
Del Río
Anna
A
Planas
Onintza
O
Sagredo
José A
JA
Ramos
Iván R
IR
Torrecillas
Leonardo
L
Pardo
Diana
D
Frechilla
Bellinda
B
Benhamú
María L
ML
López-Rodríguez
D000595:Amino Acid Sequence; D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016923:Cell Death; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000188:drug therapy / Q000473:pathology; D006624:Hippocampus / Q000166:cytology; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
C570401:2-(6-((3,4-dihydro-2H-chromen-2-ylmethyl)amino)hexyl)tetrahydro-1H-pyrrolo(1,2-c)imidazole-1,3(2H)-dione; D001578:Benzopyrans; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018696:Neuroprotective Agents; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A